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Alpha-1 Antitrypsin Deficiency

Synonyms: AAT Deficiency, A1AT Deficiency, AATD

, MD, MS, , MD, and , MD.

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Initial Posting: ; Last Revision: January 19, 2017.

Estimated reading time: 35 minutes


Clinical characteristics.

Alpha-1 antitrypsin deficiency (AATD) is characterized by an increased risk for: chronic obstructive pulmonary disease (i.e., emphysema, persistent airflow obstruction, and/or chronic bronchitis) in adults; liver disease in children and adults; panniculitis; and c-ANCA positive vasculitis. Emphysema, sometimes with associated bronchiectasis, is the most common manifestation of AATD. Smoking is the major factor influencing the course of chronic obstructive pulmonary disease (COPD). The onset of respiratory disease in smokers with AATD is characteristically between ages 40 and 50 years; in non-smokers, the onset can be delayed to the sixth decade, and some non-smokers never develop COPD. Non-smokers may have a normal life span. Although reported, emphysema in children with AATD is extremely rare. AATD-associated liver disease, which is present in only a small portion of affected children, manifests as obstructive jaundice and increased serum aminotransferase levels in the early days and months of life. The incidence of liver disease increases with age. Liver disease in adults (manifesting as cirrhosis and fibrosis) may occur in the absence of a history of neonatal or childhood liver disease. The risk for hepatocellular carcinoma (HCC) is increased in individuals with AATD.


The diagnosis of AATD relies on demonstration of low serum concentration of alpha-1 antitrypsin (AAT) and either detection of a functionally deficient AAT protein variant by protease inhibitor (PI) typing or detection of biallelic pathogenic variants in SERPINA1, the gene encoding alpha-1 antitrypsin. Note: The unconventional nomenclature of SERPINA1 alleles is based on electrophoretic protein variants that were identified long before the gene (SERPINA1) was known. Alleles were named with the prefix PI* (protease inhibitor*) serving as an alias for the gene. Using this nomenclature, the most common (normal) allele is PI*M and the most common pathogenic allele is PI*Z.


Treatment of manifestations: COPD is treated with standard therapy. Intravenous augmentation therapy (regular infusion of purified human AAT to elevate deficient serum AAT concentrations) has been recommended for individuals with established fixed airflow obstruction (especially when FEV1 is 35%-60% of predicted). Lung transplantation may be an appropriate option for individuals with end-stage lung disease. Liver transplantation is the definitive treatment for advanced liver disease. The often painful nodular lesions of panniculitis may resolve spontaneously or after dapsone or doxycycline therapy. When refractory to conventional treatment, panniculitis has responded to intravenous AAT augmentation therapy in higher than conventional doses.

Prevention of secondary complications: To lessen the progression of lung disease, yearly vaccination against influenza and pneumococcus; to lessen the risk of liver disease, vaccination against hepatitis A and B.


  • All individuals with severe AATD: Pulmonary function tests, including spirometry with bronchodilators and diffusing capacity measurements, every six to 12 months.
  • All individuals with the PI*ZZ genotype: Periodic evaluation of liver function in order to detect liver disease.
  • All persons with established liver disease: Periodic (i.e., every 6-12 months) ultrasound examination of the liver to monitor for fibrotic changes and HCC.

Agents/circumstances to avoid: Smoking (both active and passive), occupations with exposure to environmental pollutants used in agriculture, mineral dust, gas, and fumes.

Evaluation of relatives at risk: Evaluation of parents, older and younger sibs, and offspring of an individual with severe AATD in order to identify as early as possible those relatives who would benefit from institution of treatment and preventive measures.

Genetic counseling.

AATD is inherited in an autosomal recessive manner. When both parents are heterozygotes (e.g., PI*MZ), each sib of an affected individual has a 25% chance of being affected (PI*ZZ), a 50% chance of being a carrier (PI*MZ), and a 25% chance of being unaffected and not a carrier (PI*MM). In the uncommon instance in which one parent is homozygous (PI*ZZ) and one parent is heterozygous (PI*MZ), the risk to each sib of being homozygous (PI*ZZ) is 50%. Unless an individual with AATD has children with a reproductive partner who is affected or a carrier, his/her offspring will be obligate heterozygotes (carriers) for the pathogenic variant. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible once the pathogenic SERPINA1 variants have been identified in the family.


Suggestive Findings

Alpha-1 antitrypsin deficiency (AATD) should be suspected in individuals with evidence of:

  • Chronic obstructive pulmonary disease (i.e., emphysema, persistent airflow obstruction, and/or chronic bronchitis); AND/OR
  • Any of the following:
    • Liver disease at any age, including obstructive jaundice in infancy
    • C-ANCA positive vasculitis (i.e., granulomatosis with polyangiitis)
    • Necrotizing panniculitis

Confirming the Diagnosis

The diagnosis of AATD relies on A and either B or C:

A. Demonstration of low serum concentration of the protein alpha-1 antitrypsin (AAT). A variety of techniques have been used to measure serum AAT concentration; currently the most commonly used technique is nephelometry.

  • Normal serum levels are 20-53 µmol/L or approximately 100-220 mg/dL by nephelometry.
  • Serum levels observed in AATD with lung disease are usually <57 mg/dL.


(1) Serum levels of AAT may be increased in the following circumstances:

  • Up to a fourfold rise as an acute phase reactant during episodes of acute inflammation, cancer, and liver disease in individuals without AATD
  • As an acute phase reactant during episodes of acute inflammation in heterozygotes for one SERPINA1 pathogenic variant and those with mild AATD
  • In pregnancy and in women on estrogen therapy
  • In persons receiving blood transfusions or intravenous augmentation therapy (i.e., purified pooled human plasma AAT)

(2) Despite the increase in serum levels of AAT observed in these circumstances, the normally decreased serum levels of AAT in individuals with severe AATD (resulting from homozygosity for the PI*Z allele) are unlikely to rise high enough to be considered in the normal range.

B. Detection of a functionally deficient AAT protein variant by protease inhibitor (PI) typing. PI typing is performed by polyacrylamide gel isoelectric focusing (IEF) electrophoresis of serum in a gradient between pH 4 and 5.

  • Electrophoretic AAT protein variants (isoforms) are designated by letters based on their migration pattern. For example, the normal AAT protein (designated M) migrates in the middle of the isoelectric field. The abnormal AAT deficiency protein (designated Z) migrates most slowly. Other variants have been given additional alphabetic designations; some rare variants have been named by place of origin of the proband. See Table 5 (pdf).
  • Because a range of AAT protein variants from normal to deficient can be observed in an IEF assay, a reference of 13 common and five rare AAT protein variants is used to identify the specific AAT protein [Greene et al 2013].
  • The limitations of IEF include inability to interpret an atypical electrophoretic pattern resulting from rare AAT protein variants and absence of AAT protein resulting from a SERPINA1 pathogenic null allele.
  • IEF, the biochemical gold standard test for establishing the diagnosis of AATD, may be less costly than molecular genetic testing.

C. Detection of biallelic SERPINA1 pathogenic variants, which confirms a diagnosis of AATD when serum AAT levels are not measured, PI typing is not performed, or results from serum AAT levels or PI typing are discordant:

  • Molecular genetic testing may begin by a targeted approach for the most frequent SERPINA1 pathogenic variants, followed by sequence analysis and/or deletion/duplication analysis (Table 1).
    Note: The nomenclature of SERPINA1 alleles is unconventional because it is based on electrophoretic protein variants that were identified long before the gene (SERPINA1) was identified [Cox et al 1980]. Because this older nomenclature is well-established in the literature, it is used in this GeneReview.
  • SERPINA1 alleles encoding the variant AAT proteins were named with the prefix PI* (protease inhibitor*) serving as an alias for SERPINA1 (which had yet to be identified). The four SERPINA1 alleles discussed here are the following (see Molecular Genetics for more details and information on other alleles):
    • PI*M. The most common allele in all populations described to date. Some benign variants of the PI*M allele are designated M1, M2, M3, etc.
    • PI*Z. The most common pathogenic allele resulting in functionally deficient AAT protein. Individuals homozygous for PI*Z (i.e., PI*ZZ) have severe alpha-1 antitrypsin deficiency (AATD).
    • PI*S. A pathogenic allele resulting in functionally deficient AAT. It is usually of clinical consequence only in the compound heterozygous state with another pathogenic allele (e.g., PI*SZ) and when the serum AAT level is <57 mg/dL.
    • Null alleles (sometimes designated PI*QO). Pathogenic alleles that result in either no mRNA product or no protein production

Table 1.

Summary of Molecular Genetic Testing Used in Alpha-1 Antitrypsin Deficiency

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
SERPINA1Targeted analysis for pathogenic variants 295% 3
Sequence analysis 4Unknown
Deletion/duplication analysis 5Unknown, rare 6

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.


Targeted analysis for pathogenic variants is typically specific for detecting the pathogenic alleles PI*Z and PI*S. See Table 3


95% of AATD results from the pathogenic alleles PI*Z and PI*S.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Rare exon and whole-gene deletions have been reported; see HGMD in Table A, HGMD.

Testing Strategy

Though the optimal algorithm for laboratory testing is not well defined, guidelines for the diagnosis and management of AATD by the American Thoracic Society/European Respiratory Society include recommended indications for genetic testing for AATD [American Thoracic Society & European Respiratory Society 2003].

Table 2.

Clinical Indications for Genetic Testing

Clinical IndicationGenetic Testing
RecommendedTo be Decided in Discussion w/PatientNot RecommendedDiscouraged
Symptomatic adult w/emphysema, COPD, asthma w/incompletely reversible airflow obstructionx
Asymptomatic w/persistent obstruction & risk factorsx
Symptomatic adult w/emphysema, COPD, asthma w/incompletely reversible airflow obstruction (in countries with prevalence < N America or Europe)x
Adults with bronchiectasis w/out evident etiologyx
Adolescents w/persistent airflow obstructionx
Asymptomatic w/persistent airflow obstruction & no risk factorsx
Adults w/asthma & completely reversible airflow obstructionx
Unexplained liver diseasex
Adult w/necrotizing panniculitisx
Adult w/c-ANCA positive vasculitisx
Sib of adult w/AATDx
Family history of COPD or liver disease not known to be caused by AATDx
Distant relative of an individual w/the PI*ZZ genotypex
Offspring/parent of an individual w/the PI*ZZ genotypex
Sib, offspring, parent, or distant relative of a heterozygous individual (e.g., w/the PI*MZ genotype)x
Carrier status assessment for reproduction planning
Individual at high risk for AAT deficiency-related diseasex
Partner of individual w/the PI*ZZ genotype or the PI*MZ genotypex
Population screening
In countries w/AATD prevalence >1:1500, prevalent smoking, & adequate counseling servicesx
In smokers with normal spirometryx
In countries w/low AATD prevalence, low prevalence of smoking, or inadequate counseling servicesx
Predispositional testingx
Predispositional fetal testingx

Clinical Characteristics

Clinical Description

Alpha-1 antitrypsin deficiency (AATD) can present with hepatic dysfunction in individuals from infancy to adulthood and with obstructive lung disease and/or bronchiectasis, characteristically in individuals older than age 30 years. Phenotypic expression varies within and between families.

The severity of AATD depends on the genotype and resultant serum AAT level. Individuals homozygous for severe deficiency alleles (i.e., PI*ZZ) have low serum AAT levels, placing them at increased risk for chronic obstructive pulmonary disease (COPD) (see Table 3). Individuals with alleles associated with intra-hepatic inclusions (e.g., Z, Mmalton) are also at increased risk of developing liver disease.

Lung Disease

Adult-onset lung disease. Chronic obstructive pulmonary disease (COPD), specifically emphysema and/or chronic bronchitis, is the most common clinical manifestation of AATD.

In adults, smoking is the major factor that can accelerate the development of COPD. Although the natural history of AATD varies, depending in part on what has brought the patient to medical attention (e.g., lung symptoms, liver symptoms, asymptomatic relative of an affected individual), the onset of respiratory disease in smokers with AATD is characteristically between ages 40 and 50 years [Tanash et al 2008]. Non-smokers may have a normal life span, but can also develop lung and/or liver disease.

Patients with severe AATD may manifest the usual signs and symptoms of obstructive lung disease, asthma, and chronic bronchitis (e.g., dyspnea, cough, wheezing, and sputum production) [McElvaney et al 1997]. For example, in the National Heart, Lung, and Blood Institute (NHLBI) Registry, with 1129 participants with severe deficiency of AAT, 84% described dyspnea, 76% wheezed with an upper respiratory tract infection, and 50% reported cough and phlegm [McElvaney et al 1997, Eden et al 2003]. Of note, the prevalence of AATD in persons with asthma does not differ from that found in the general population [Wencker et al 2002, Miravitlles et al 2003].

Most (~95%) of individuals with severe AATD have evidence of bronchiectasis on chest CT, with 27% demonstrating clinical symptoms of bronchiectasis [Parr et al 2007].

In individuals with AATD:

  • Chest CT shows loss of lung parenchyma and hyperlucency. In contrast to the usual pattern observed in centriacinar emphysema (emphysematous changes more pronounced in the lung apices than bases), the pattern observed in two thirds of individuals with AATD is that of more pronounced emphysematous changes in the bases than apices [Parr et al 2004].
  • Lung function tests show decreased expiratory airflow, increased lung volumes, and decreased diffusing capacity. Approximately 60% of patients with AATD-associated emphysema demonstrate a component of reversible airflow obstruction, defined as a 200 mL and 12% increase in the post-bronchodilator FEV1 and/or FVC.

Under-recognition of AATD often causes a long delay between first symptoms and initial diagnosis of AATD (i.e., 5-7 years) and many patients report seeing multiple physicians before the diagnosis is first established.

Childhood-onset lung disease. Although reported, emphysema in children with AATD is extremely rare and may result from the coexistence of other unidentified genetic factors affecting the lung [Cox & Talamo 1979].

Studies that followed newborns with severe AAT deficiency through age 32 years showed that most adults did not smoke and lacked physiologic and CT evidence of emphysema [Bernspång et al 2009]. Longer term follow-up studies are not currently available. In most observational studies, the mean age of individuals with lung disease is in the fifth decade [Seersholm et al 1997, AADRSG 1998].

Risk for lung disease in PI*MZ heterozygotes. Approximately 3% of North Americans are PI*MZ heterozygotes. PI*MZ heterozygotes are generally not considered to be at significantly increased risk for clinical emphysema; however, meta-analyses suggest the possibility of a subpopulation of PI*MZ heterozygotes at risk for accelerated lung disease [Hersh et al 2004, Sørheim et al 2010]. Of note, slight abnormalities of lung function can be present without clinical symptoms. Emerging information also suggests that emphysema may be present on chest CT without evidence of impaired lung function on pulmonary function tests [Smith et al 2014].

Risk for lung disease in persons with the PI*SZ genotype. Individuals who smoke and have the PI*SZ genotype with serum AAT levels below the protective threshold value have a slightly increased disease risk, especially if they smoke.

Table 3.

Relationship of AAT Protein Variants to Serum AAT Levels and Emphysema Risk in Adults

AAT Protein VariantsPrevalence (%)Serum AAT LevelsEmphysema Risk
WorldwideNorth AmericaEurope"True Level" 1 Mean (5th %ile–95th %ile)Commercial Standard 2 Median (5th %ile–95th %ile)
MM96.393.091.133 (20–53)147 (102–254)Background
MS2.74.86.633 (18–52)125 (86–218)Background
MZ0.82.11.925.4 (15–42)90 (62–151)Background
SS0.080.10.328 (20–48)95 (43–154)Background
SZ0. (10–23)62 (33–108)20%-50%
ZZ0.0030.010.015.3 (3.4–7)≤29 (≤29–52)80%-100%

Note: An attempt to correlate serum AAT levels with protein variants in children showed trends similar to those seen in adults [Donato et al 2012].

Liver Disease

Childhood-onset liver disease. The most common manifestation of AATD-associated liver disease is jaundice, with hyperbilirubinemia and raised serum aminotransferase levels in the early days and months of life.

Liver abnormalities develop in only a portion of children with AATD. In a study of 200,000 Swedish children who were followed up after newborn screening for AATD, 18% of those with the PI*ZZ genotype developed clinically recognized liver abnormalities and 2.4% developed liver cirrhosis with death in childhood [Sveger 1976, Sveger 1988]. Liver damage may progress slowly [Volpert et al 2000].

In a follow-up study of 44 children with AATD-associated liver disease initially manifesting as cirrhosis or portal hypertension, outcomes ranged from liver transplantation in two, to relatively healthy lives up to 23 years after diagnosis in seven [Migliazza et al 2000].

It is not known why only a small proportion of children with early hyperbilirubinemia have continued liver destruction leading to cirrhosis. The overall risk that an individual with the PI*ZZ genotype will develop severe liver disease in childhood is generally low (~2%); the risk is higher among sibs of a child with the PI*ZZ genotype and liver disease.

  • When liver abnormalities in the proband are mild and resolve, the risk of liver disease in sibs with the PI*ZZ genotype is approximately 13%.
  • When liver disease in the proband is severe, the risk for severe liver disease in sibs with the PI*ZZ genotype may be approximately 40% [Cox 2004].

Adult-onset liver disease. Liver disease in adults (manifesting as cirrhosis and fibrosis) may occur in the absence of a history of neonatal or childhood liver disease. Liver disease is more common in men than women.

In an early series of 246 individuals with the PI*ZZ genotype, liver disease was observed in 12%. In other series, between 15% and 19% of individuals over age 50 years with AATD and the PI*ZZ genotype developed cirrhosis. The risk for liver disease at age 20-40 years is approximately 2% and at age 41-50 years approximately 4% [Cox & Smyth 1983].

Later autopsy studies suggest that the prevalence of liver disease may be as high as 40% in older individuals who have never smoked and do not have COPD [Eriksson 1987].

Hepatocellular carcinoma (HCC). The risk for HCC among individuals with AATD and the PI*ZZ genotype is several times that typically associated with liver cirrhosis. The incidence of hepatocellular carcinoma is estimated at more than 1.5% per year [Bruix et al 2005]. This increased risk has been attributed to failure of apoptosis of injured cells with retained Z protein, which sends a chronic regeneration signal to hepatocytes with a lesser load of retained Z protein [Perlmutter 2006].

Liver pathology. AATD liver inclusions are visualized as bright pink globules of various sizes, using periodic acid-Schiff (PAS) stain following diastase treatment (PAS-D). The extent of inclusion formation varies considerably; the number and size of liver inclusions increases with age. Inclusions are not observed before age 12 weeks. Note: Liver biopsy, when indicated in the evaluation of patients with liver disease, may show periodic Schiff (PAS) positive diastase-resistant inclusion bodies which are suggestive of but not pathognomonic for AATD.

In infants with AATD, inclusions may be fine and granular and difficult to identify in percutaneous liver biopsy specimens. They are also observed in bile duct epithelium [Cutz & Cox 1979].

Histopathologic features of childhood-onset liver disease include intrahepatic cholestasis, varying degrees of hepatocellular injury, and moderate fibrosis with inflammatory cells in portal areas.

Because liver inclusions indicate the presence of at least one PI*Z allele, histologic examination of the liver cannot distinguish between individuals who are PI*MZ heterozygotes and PI*ZZ homozygotes. Furthermore, visualization of inclusions may be variable among PI*MZ heterozygotes.

The PI*MZ and PI*SZ genotypes are not associated with an increased risk for childhood liver disease; however, on occasion, elevated levels of liver enzymes that resolve have been observed. In a study of 58 heterozygous children showing signs of liver involvement during the first six months of life, almost all had normal values of liver enzymes at ages 12 months, five years, and ten years [Pittschieler 2002].

Among adults presenting with chronic liver failure, a greater number of PI*MZ heterozygotes (8.4%) was observed than were reported in the general population (2%-4%) [Graziadei et al 1998]. Better characterization of the risk for liver disease among PI*MZ heterozygotes must await longitudinal studies.

Other Disease Associations

While a variety of other illnesses have been observed in individuals with AATD (e.g., membranoproliferative glomerulonephritis, aneurysms, inflammatory bowel disease), only panniculitis and c-ANCA-positive vasculitis have been systematically associated with AATD.

  • Panniculitis occurs in an estimated one in 1000 individuals with AATD [AADRSG 1998]. Panniculitis characteristically presents as migratory, inflammatory, tender skin nodules which may ulcerate [Stoller & Piliang 2008]. Sites of trauma (e.g., legs, lower abdomen) are most commonly affected. Presumably like emphysema in the lung, panniculitis in the skin is caused by unopposed proteolytic damage produced by the PI*Z allele.
  • C-ANCA-positive vasculitis (e.g., polyangiitis with granulomatosis; previously called Wegener granulomatosis). Variant SERPINA1 alleles are many-fold more prevalent in individuals with c-ANCA-positive vasculitis than in controls: for persons with polyangiitis with granulomatosis the odds ratio for the PI*MZ or PI*MS genotypes was 1.47 compared to the PI*MM genotype, and the odds ratio for the PI*ZZ, PI*SS, or PI*SZ genotypes was 14.6 compared to the PI*MM genotype.

Genotype-Phenotype Correlations

The risk for lung disease associated with the following SERPINA1 genotypes is summarized in Table 3.

PI*MM. This genotype is associated with a normal serum concentration of AAT and no increased risk of liver or lung disease.

PI*MZ. In general, individuals with this genotype (especially non-smokers) are not considered to be at increased risk for lung disease. Some emerging data suggest that a subset of individuals with the PI*MZ genotype may experience accelerated lung destruction, especially if they are smokers.

PI*SS. This genotype does not appear to be associated with an increased risk for clinical disease [Ferrarotti et al 2012]. The S allele is most common among individuals of Iberian descent.

PI*SZ. This genotype is not usually associated with a high risk for liver or lung disease; however, the 20% of individuals with the PI*SZ genotype whose serum AAT levels are below the protective threshold value (57 mg/dL) are at increased risk for lung disease, especially if they are smokers [Turino et al 1996].

PI*ZZ. Individuals with this genotype have a serum concentration of AAT that is approximately 10%-20% of normal (serum levels of 20-35 mg/dL) and are at high risk for both liver and lung disease. This genotype is present in 95% of affected individuals with clinical manifestations of AATD. Variable disease expressivity in individuals with the PI*ZZ genotype – not accounted for by the presence of known risk factors such as cigarette smoking – suggests the existence of other as-yet unidentified genetic disease modifiers.

PI*null-null (sometimes designated PI*QO). Individuals with this genotype have no measurable serum AAT secondary to complete lack of synthesis of AAT. Because protein does not accumulate in the liver, these individuals are not at increased risk of developing liver disease; however, they are at high risk of developing lung disease.


SERPINA1 genotypes (e.g., PI*ZZ) associated with serum AAT levels below the protective threshold value of 57 mg/dL are considered to confer an increased risk of developing lung disease. Although inflammatory insults to the lung such as smoking or occupational exposures can accelerate lung disease, disease expression may still vary. Genetic modifiers that remain poorly understood (e.g., IL10 single-nucleotide variants) likely account for some of this variability [Demeo et al 2008]. Furthermore, the designation of the "protective threshold" value of 57 mg/dL has been empirically assigned and, though it has provided generally helpful clinical guidance in defining pulmonary risk, may do so imperfectly.

Individuals with SERPINA1 alleles associated with intra-hepatic inclusions (because of abnormal protein folding during translation and resultant intra-hepatocyte polymerization, e.g., Z, Mmalton) are also at risk for developing liver disease.


In some publications, the term alpha-1-protease inhibitor is substituted for alpha-1 antitrypsin (AAT).


AATD is one of the most common metabolic disorders in persons of northern European heritage, occurring in approximately one in 5,000-7,000 individuals in North America and one in 1,500-3,000 in Scandinavia. AATD also occurs (in lower frequencies) in all other racial subgroups worldwide [Campbell 2000, Miravitlles 2000, de Serres & Blanco 2012].

Within Europe, the highest prevalence of the PI*Z allele is observed in northern and western countries (mean allele frequency of 0.0153), gradually decreasing throughout the rest of Europe in a north-to-south gradient, with the lowest prevalence in eastern Europe (0.0092).

The frequency of the PI*S allele is the highest in southern Europe (0.0564), decreasing in northern Europe (0.0176) [Luisetti & Seersholm 2004, de Serres & Blanco 2012].

In an analysis estimating the prevalence of various SERPINA1 genotypes in 97 countries (out of 193 countries worldwide), a worldwide total of 181,894 individuals with the PI*ZZ genotype was expected, with nearly 70% of all PI*ZZ genotypes estimated to be in Europe and North/Central America. Northern and central Europe account for 74,000 (41% of the total) and North America for 44,000 (24% of the total). Similarly, 48% of all the PI*SZ genotypes were also estimated to be in northern and central Europe, 20% in North America and Central America, and 16% in South America [de Serres & Blanco 2012].

Despite the clustering of geographic areas with low or high prevalence of the PI*S and PI*Z deficiency alleles, that prevalence is not necessarily shared in immediately adjacent countries [de Serres & Blanco 2012]. Populations with intermarriage naturally may reflect allele frequencies and disease prevalences in the contributing groups. Although deficiency alleles have been described in Asian and African populations (e.g., PI*Siiyama), the PI*ZZ genotype is generally rare in these groups [de Serres & Blanco 2012].

Differential Diagnosis

Lung disease. Alpha-1 antitrypsin deficiency (AATD) appears in the differential diagnosis of chronic obstructive pulmonary disease (COPD), including: emphysema, chronic bronchitis, and bronchiectasis.

Liver disease. AATD appears in the differential diagnosis of chronic hepatitis and cirrhosis. Other diseases to consider include chronic viral hepatitis, hereditary hemochromatosis (see HFE-Associated Hereditary Hemochromatosis, Juvenile Hereditary Hemochromatosis), Wilson Disease, non-alcoholic steatohepatitis (NASH), and primary biliary cirrhosis.

In a study of 85 children with neonatal cholestasis, AATD was among the most common diagnoses (11/85); others were extrahepatic biliary atresia (30/85) and progressive familial intrahepatic cholestasis (11/85) (see ATPB1 Deficiency) [Fischler et al 2001a, Fischler et al 2001b].

PI*Z allele frequency was also high (12%) in a group of 29 individuals with cholestatic jaundice and cirrhosis, when compared with controls (0.5%) [Lima et al 2001].


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with alpha-1 antitrypsin deficiency (AATD), the following evaluations of lung, liver, skin, and vasculature are recommended:

  • Lungs
    • Pulmonary function tests, including spirometry (with post-bronchodilator testing), lung volumes, diffusing capacity, and measures of oxygenation
    • Chest CT, which is more sensitive for detecting emphysema than pulmonary function tests [Stolk et al 2001], as part of the initial evaluation by some clinicians
  • Liver. Liver biopsy for light microscopy and histochemistry when definition of the precise nature and extent of liver disease is clinically indicated [Nelson et al 2012]
  • Skin. A detailed history and physical examination to assess for panniculitis

Treatment of Manifestations

Lung Disease

Patients with obstructive lung disease should receive standard therapy for chronic obstructive pulmonary disease (COPD) which may include bronchodilators, inhaled corticosteroids, pulmonary rehabilitation, supplemental oxygen, and vaccinations (e.g., influenza and pneumococcal).

Specific therapy for AATD-related lung disease, called augmentation therapy, is the periodic intravenous infusion of pooled human serum alpha-1antitrypsin (AAT). Concordant observational studies show that AAT augmentation therapy can slow the rate of FEV1 decline among individuals with AATD-related emphysema [Seersholm et al 1997, AADRSG 1998, Wencker et al 1998, Tonelli et al 2009].

  • Two placebo-controlled randomized controlled trials [Dirksen et al 1999, Dirksen et al 2009] have shown trends toward preservation of lung density as determined by chest CT in treated individuals vs. controls.
  • Results from a third placebo-controlled randomized, clinical trial are pending; however, preliminary findings are consistent with slowing of progression of emphysema [Chapman et al 2013].

Guidelines available from the American Thoracic Society & European Respiratory Society [2003] and from the Canadian Thoracic Society [Marciniuk et al 2012]:

  • Recommend intravenous AAT augmentation therapy for individuals with established emphysema. Of note, the greatest benefit evident is observed in individuals with moderate degrees of airflow obstruction (e.g., FEV1 35%-60% predicted).
  • Do not recommend prophylactic treatment with intravenous AAT augmentation therapy for individuals with severe AATD but no demonstrable emphysema.

In addition, the Canadian Thoracic Society guidelines specify that AAT augmentation therapy should be offered to individuals with AATD and evidence of emphysema only when they have stopped smoking and have demonstrated accelerated loss of lung function despite optimal therapy for COPD.

AATD-related lung disease can be modified in asymptomatic individuals by lifestyle changes, including avoidance of smoking and occupations with exposure to environmental pollutants. It is suspected that regular exercise and good nutrition help maintain lung health.

Approximately 8% of lung transplants in the US are performed in individuals with COPD related to AATD. Lung transplantation may be an appropriate option for individuals with end-stage lung disease (i.e., FEV1 <30%) and severe functional impairment despite optimal therapy [Seersholm et al 1994, Trulock 1998]. Some evidence suggests that among comparably affected individuals with AATD, those who receive a lung transplant survive longer (median survival of 11 years in transplant recipients compared to 5 years in those who do not receive a transplant) [Tanash et al 2011].

Note: Though effective in specific subsets of patients with AAT-replete COPD [Fishman et al 2003], lung volume reduction surgery confers smaller and shorter-lived improvements in lung function in patients with AATD, and so is not generally recommended [Stoller et al 2007].

Liver Disease

Vitamin E therapy improves liver function in infants with the PI*MZ genotype and in children with cholestasis [Sokol et al 1986, Pittschieler 1991], and could be predicted to help prevent oxidative damage to the lungs. Nonetheless, firm evidence that antioxidant therapy (like Vitamin E) is beneficial in AATD is lacking.

Liver transplantation, the definitive surgical treatment for advanced liver disease, can restore serum AAT levels to normal because a liver from a donor with a PI*MM genotype produces qualitatively and quantitatively normal AAT [Francavilla et al 2000]. Serial lung function measurements following liver transplantation have been studied in a small number of patients to date (N = 17) with a highly variable course following liver transplant [Carey et al 2013]. Overall, 65% of patients experienced a decline in FEV1 post-liver transplant with the mean decline being modest over an average of 49.2 months post-liver transplant and not achieving statistical significance.

The risk for childhood-onset liver disease in infants with the PI*ZZ genotype who are breast-fed during the first month of life was reported to be reduced; however, breast-feeding does not confer absolute protection against the development of severe liver disease [Sveger 1985].


Panniculitis. The often painful nodular lesions of panniculitis may resolve spontaneously or after dapsone or doxycycline therapy [Yesudian et al 2004]; however, when panniculitis is refractory to conventional treatment, it has been shown (anecdotally) to respond to intravenous AAT augmentation therapy in doses higher than the conventional dose of 60 mg/kg [Stoller & Piliang 2008]. Of note, it is presumed that the panniculitis improves because AAT augmentation therapy restores the proteolytic screen in the skin, thereby lessening inflammation.

Prevention of Secondary Complications

To lessen the progression of lung disease, the following are recommended:

  • Complete cessation of smoking
  • Avoidance of dusty occupational exposures
  • Yearly vaccination against influenza and pneumococcus

To lessen the risk of liver disease, the following are recommended:


Patients with severe AATD should undergo pulmonary function tests (including spirometry with bronchodilators and diffusing capacity measurements) every six to 12 months [American Thoracic Society & European Respiratory Society 2003].

All individuals with the PI*ZZ genotype (including those who did not manifest liver disease in childhood) should undergo periodic evaluation of liver function [American Thoracic Society & European Respiratory Society 2003].

While current guidelines from the American Thoracic Society recommend regular follow up of liver function tests in adults with AATD [American Thoracic Society & European Respiratory Society 2003], those tests may not reliably detect liver disease in these individuals [Clark et al 2012]. For instance, various liver function tests were not significantly different in persons with AATD with or without liver disease, and the sensitivity of the alanine transaminase (ALT) for alpha-1 antitrypsin-associated liver disease was only 12% [Clark et al 2012]

A combination of liver function tests, platelet count, and liver ultrasound examination may be an effective screening method to detect the presence of severe fibrosis or cirrhosis [Dawwas et al 2013].

All patients with established liver disease should have periodic (i.e., every 6-12 months) ultrasound examination of the liver to monitor for fibrotic changes and HCC [American Thoracic Society & European Respiratory Society 2003, Nelson et al 2012].

Agents/Circumstances to Avoid

Smoking (both active and passive) is a risk factor for lung disease in individuals with AATD.

Occupational exposure (including exposure to environmental pollutants used in agriculture, mineral dust, gas, and fumes) is an independent risk factor for lung function impairment in individuals with the PI*ZZ genotype.

Evaluation of Relatives at Risk

The ATS/ERS guidelines recommend evaluation of older and younger sibs of an individual with severe AATD (Table 2) in order to identify as early as possible those who would benefit from institution of treatment and preventive measures.

The ATS/ERS guidelines also recommend testing for parents and children of individuals with severe AATD.

Extended pedigree analysis beyond first-degree relatives may be indicated in selected instances. For example, the presence of an AATD-associated condition (e.g., COPD, liver disease, panniculitis) in a more distant family member would justify extensive family testing (i.e., of family members beyond parents, sibs, and offspring).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Management of women with AATD during pregnancy should be guided by usual care principles, both for women without clinical disease and for those with liver disease. As noted, emphysema, especially in non-smokers, would not commonly be expected during the usual childbearing age range.

Therapies Under Investigation

Inhaled administration of purified AAT can restore AAT levels in the bronchoalveolar fluid. Older studies demonstrated the feasibility of inhaling pooled human plasma-derived AAT –currently the subject of ongoing study [Hubbard & Crystal 1990, Sandhaus 2004, Abusriwil & Stockley 2006].

Synthetic inhibitors of human neutrophil elastase, administered intravenously and orally, could theoretically provide protection against proteolytic lung damage. No such drug has yet been approved.

Antioxidant therapy. Vitamins A, C, and E and N-acetylcysteine have been suggested in the treatment of AATD-related emphysema. The efficacy of such treatment has not been evaluated [Sandhaus 2004].

Synthetic chaperones and polymerization could potentially prevent the intracellular polymerization of AAT implicated in causing intra-hepatocyte inclusions and liver disease. Modest improvement in liver retention and increase in plasma concentrations of AAT was suggested after administration of 4-phenyl-butyric acid (PBA) [Burrows et al 2000]. However, a human randomized trial failed to demonstrate efficacy of 4-PBA [Teckman 2004].

Biochemical data on a peptide that specifically binds to variant AAT encoded by the PI*Z allele and that inhibits polymerization are promising, but future cellular and animal studies are needed [Mahadeva et al 2002, Parfrey et al 2004].

Gene therapy is aimed at introducing a functional copy of SERPINA1 into cells to allow production of a normal AAT protein. An alternative approach is to introduce gene(s) to turn off production of the endogenous abnormal variant protein encoded by the pathogenic SERPINA1 allele. Murine studies transfecting muscle with an adeno-associated virus vector carrying a normal functional human SERPINA1 allele have been promising. Human gene therapy studies are currently under way, with evidence that this approach can sustainably increase serum AAT levels, albeit not yet to therapeutic levels (i.e., exceeding 57 mg/dL, the serum protective threshold value) [Flotte et al 2011].

Drugs to enhance autophagy (e.g., rapamycin and carbamazepine) have shown promise in enhancing serum AAT levels and diminishing liver damage. Human trials are under way; results are pending [Hidvegi et al 2010, Kaushal et al 2010, Perlmutter 2011].

Search in the US and in Europe for access to information on clinical studies for a wide range of diseases and conditions.


Lung volume reduction surgery (LVRS) performed for persons with advanced non-AATD emphysema can (in appropriately selected individuals) improve lung function and enhance survival [Fishman et al 2003]. However, in AATD-associated emphysema, the physiologic improvement following LVRS is more modest and less sustained than in non-AATD COPD [Gelb et al 1999, Stoller et al 2007]. In a study of 12 individuals with AATD-associated emphysema, postoperative lung function returned to baseline in six to 12 months but showed further deterioration in 24 months [Cassina et al 1998]. Results of the National Emphysema Treatment Trial were similarly unfavorable [Stoller et al 2007]; thus, LVRS is generally not recommended for individuals with AATD [American Thoracic Society & European Respiratory Society 2003].

Transgenic/recombinant production of human AAT protein could solve the potential problems of limited supply of AAT purified from human serum and the theoretic transmission of infectious agents. However, past clinical trials of transgenic/recombinant AAT produced in sheep and goats [Casolaro et al 1987, Wright et al 1991, Ziomek 1998] were discontinued because of serious immunologic reactions in the lungs of recipients. Results from more recent studies are not currently available.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The disorder alpha-1 antitrypsin deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an individual with ATTD have at least one pathogenic allele and are usually heterozygous for a PI*Z allele (e.g., PI*MZ or PI*SZ); less frequently, a parent may be homozygous for the PI*Z allele (i.e., PI*ZZ).
  • Clinical disease is uncommon in heterozygotes (Table 3).

Sibs of a proband. Risk to sibs depends on the genetic status of the parents.

  • If both parents are heterozygous (e.g., PI*MZ) for a pathogenic allele, each sib of an affected individual has a 25% chance of being affected (i.e., PI*ZZ), a 50% chance of being an asymptomatic carrier (i.e., PI*MZ), and a 25% chance of being unaffected and not a carrier (i.e., PI*MM).
  • If one parent is homozygous (i.e., PI*ZZ) for a pathogenic allele and the other parent is heterozygous (e.g., PI*MZ) for a pathogenic allele, each sib has a 50% chance of being affected (i.e., PI*ZZ) and a 50% chance of being an asymptomatic carrier (e.g., PI*MZ).
  • Molecular genetic testing should be offered to all sibs in order to clarify their genotype (Table 2).

Offspring of a proband

  • Unless an individual with AATD has children with a reproductive partner who is affected or a carrier, his/her offspring will be obligate (unaffected) heterozygotes (carriers) (e.g., PI*MZ).
  • In populations with a high carrier frequency and/or a high rate of consanguinity, the reproductive partner of the proband may also have one or more SERPINA1 pathogenic alleles. Thus, the risk to offspring is most accurately determined after protease inhibitor (PI) typing by isoelectric focusing of serum or SERPINA1 molecular genetic testing of the proband's reproductive partner.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier (e.g., PI*MZ).

Carrier Detection

Carrier testing by protease inhibitor (PI) typing by isoelectric focusing of serum or SERPINA1 molecular genetic testing is possible for sibs and offspring of affected individuals.

Note: Measurement of serum AAT level is not reliable for determining carrier status because the range of serum AAT levels among most carriers may overlap the normal serum range [Bornhorst et al 2013].

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Risk to sibs of developing severe liver disease in infancy. Although the age of onset, severity, type of symptoms, and rate of progression of AATD cannot be predicted in sibs based on genotype some estimates are available on the risk to sibs of developing severe liver disease in infancy [Cox 2004].

  • If the parents are carriers (e.g., PI*MZ) but have not had a child with severe liver disease, the risk to offspring of having AATD (25%) AND severe liver disease in childhood (13.6%) is less than 1% (0.64%).
  • If an affected individual died from severe liver disease in childhood, the risk to sibs of having AATD (25%) AND severe liver disease in childhood (40%) is 10%.
  • If an affected individual did not have severe liver disease in childhood or if the liver disease resolved, the risk to sibs of having AATD (25%) AND liver disease (13%) is 3.3%.

Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the SERPINA1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for AATD are possible.

Note: Prenatal testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression of the disorder. Fetal testing is not recommended in the American Thoracic Society/European Respiratory Society guidelines because of the variable expressivity of disease and the possibility that individuals with severe deficiency of AAT can have a normal life span and escape disease, especially if they never smoke [American Thoracic Society & European Respiratory Society 2003].

Because some children with AATD develop severe liver disease in the newborn period, and some of these children have a poor outcome, prenatal diagnosis may be of interest to some at-risk couples who have previously had a child with severe liver disease (see Related Genetic Counseling Issues, Risk to sibs of developing severe liver disease in infancy).


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Alpha-1 Advocacy Alliance
    103 Rapidan Church Lane
    PO Box 202
    Wolftown VA 22748
    Phone: 866-367-2122 (toll-free); 540-948-6777
    Fax: 540-948-6763
  • Alpha-1 Association
    2937 Southwest 27 Avenue
    Suite 106
    Miami FL 33133
    Phone: 800-521-3025 (toll-free); 305-648-0088
    Fax: 305-648-0089
  • Alpha-1 Association Genetic Counseling Program
    The center offers free and confidential genetic counseling to families with Alpha-1 Antitrypsin Deficiency.
    Alpha-1 Association
    2937 SW 27 Avenue
    Suite 106
    Miami FL 33133
    Phone: 800-785-3177 (toll-free)
  • Alpha-1 Canada
    1638 Northway Avenue
    Windsor Ontario N9B 3L9
    Phone: 888-669-4583 (toll-free); 519-258-1444
    Fax: 519-258-1614
  • Alpha-1 Foundation
    3300 Ponce de Leon Boulevard
    Coral Gables FL 33134
    Phone: 877-228-7321; 305-567-9888
    Fax: 305-567-1317
  • My46 Trait Profile
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • American Liver Foundation
    75 Maiden Lane
    Suite 603
    New York NY 10038
    Phone: 800-465-4837 (Toll-free HelpLine); 212-668-1000
    Fax: 212-483-8179
  • Canadian Liver Foundation (CLF)
    2235 Sheppard Avenue East
    Suite 1500
    Toronto Ontario M2J 5B5
    Phone: 800-563-5483 (toll-free); 416-491-3353
    Fax: 416-491-4952
  • Childhood Liver Disease Research and Education Network (ChiLDREN)
    Phone: 720-777-2598
  • Children's Liver Disease Foundation (CLDF)
    36 Great Charles Street
    Birmingham B3 3JY
    United Kingdom
    Phone: +44 (0) 121 212 3839
    Fax: +44 (0) 121 212 4300
  • Metabolic Support UK
    5 Hilliards Court, Sandpiper Way
    Chester Business Park
    Chester CH4 9QP
    United Kingdom
    Phone: 0845 241 2173
  • National Organization for Rare Disorders (NORD)
    Phone: 800-999-6673
  • Alpha-1 Canadian Registry
    Toronto Western Hospital
    399 Bathurst Street
    7th Floor, East Wing, Room 445
    Toronto Ontario M5T 2S8
    Phone: 800-352-8186 (toll-free); 416-603-5020
    Fax: 416-603-5020
  • Alpha-1 Foundation - National and International Registries
    Phone: 800-245-6809

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Alpha-1 Antitrypsin Deficiency: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Alpha-1 Antitrypsin Deficiency (View All in OMIM)


Molecular Genetic Pathogenesis

The basis for pulmonary disease in alpha-1 antitrypsin deficiency (AATD) is a reduced inhibition of neutrophil elastase that is always in the lung (and increased in smokers), resulting in excessive destruction of the elastin in the alveolar walls. Thus, lung disease is considered to result from a "toxic loss of function."

In contrast, liver disease in AATD is deemed the result of a "toxic gain of function" in which AAT encoded by pathogenic SERPINA1 alleles polymerizes within the hepatocyte (through a mechanism called "loop-sheet polymerization") [Carrell & Lomas 2002], precluding secretion and allowing intra-hepatocyte accumulation of AAT protein. Through incompletely understood mechanisms, this accumulation of AAT protein is associated with liver disease. Ineffective clearance of abnormal AAT protein from the hepatocyte by protein chaperones has been suggested as a factor contributing to the liver disease [Kopito & Ron 2000, Perlmutter 2002]. Of note, the role of enhancing autophagy in the liver (e.g., by administering carbamazepine or rapamycin) is being actively investigated [Hidvegi et al 2010, Kaushal et al 2010, Perlmutter 2011].

While uncertain, the pathogenic mechanism of polyangiitis with granulomatosis may relate to unopposed expression of c-ANCA, a substrate for AAT [Mahr et al 2010].

Gene structure. SERPINA1 comprises five exons and has a total length of 12.2 kb. There are two promoters, with one controlling expression in macrophages. Multiple transcript variants are reported; however, they all encode the same AAT protein (for an explanation of nomenclature, see Diagnosis, Electrophoretic ATT protein variants (isoforms) and Detection of a functionally deficient AAT protein variant by protease inhibitor typing). For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Many benign variants of SERPINA1, which have no disease association, have been described. Benign variants of the normal PI*M allele (e.g., PI*M1, PI*M2) have also been described.

The normal PI*M allele is prevalent in some populations, particularly in Italy, and usually occurs in the compound heterozygous state with the PI*S allele (i.e., PI*MS), as seen in approximately 8% of persons of northern European heritage.

Pathogenic variants. Ninety-five percent of AATD-related disease results from homozygosity for the common SERPINA1 PI*Z deficiency alleles (i.e., PI*ZZ).

At least 20 rare deficiency alleles and at least 14 null alleles, found in many populations, comprise the remaining 5% of deficiency alleles.

  • The protein product of PI*Mmalton, like the protein product of the PI*Z allele, aggregates in the liver (Table 4).
  • Other deficiency alleles include PI*Siiyama (Table 4).
  • SERPINA1 null alleles do not produce detectable serum AAT protein.

Table 4.

SERPINA1 Pathogenic Variants Discussed in This GeneReview

SERPINA1 Common Allele NameDNA Nucleotide ChangePredicted Protein Change
(Common Designation 1)
Reference Sequence

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Commonly used protein designations that do not conform to current naming conventions, which include the signal sequence of the reference protein NP_000286​.3 thereby increasing the amino acid codon number by 24 amino acids for each variant.

See Table 5 (pdf) for additional information on selected SERPINA1 variants.

Normal gene product. Alpha-1 antitrypsin (AAT), a 52-kd glycoprotein, is a member of the serum protease inhibitor (serpin) family. The molecule is composed of 418 amino acids; the first 24 are the signal peptide, while residues 25-418 encode the mature protein. AAT provides >90% of the protection against neutrophil elastase in the lower airways.

Abnormal gene product. The Z protein variant (encoded by the PI*Z allele) polymerizes within the hepatocyte before being secreted. Polymers of Z protein variants are also produced by alveolar macrophages and have been shown to be chemotactic for neutrophils. Thus, in addition to being ascribed to a "toxic loss of function" mechanism, lung destruction may be fueled by an inflammatory reaction related to the polymers of Z protein variants in the lung [McElvaney et al 1997].

Other protein variants, such as the S variant protein encoded by the PI*S allele, are more easily degraded.

Others are not translated because of unstable mRNA (RNA decay), are truncated and rendered nonfunctional, or may cause conformational change, leading to intracellular polymerization.

Null variant alleles do not produce serum AAT [Brantly et al 1988, Cox & Billingsley 1989, Faber et al 1994].


Published Guidelines / Consensus Statements

  • American Thoracic Society, European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Available online. 2003. Accessed 3-1-18.
  • 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; Canadian Thoracic Society COPD Clinical Assembly Alpha-1 Antitrypsin Deficiency Expert Working Group. Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: A Canadian Thoracic Society clinical practice guideline. 2012. [PMC free article: PMC3373286] [PubMed: 22536580]

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Chapter Notes

Author Notes

Research Support, Non-US Government
Research Support, US Government, PHS
Review. Thorax. 2004;59:843-9

Author History

Loutfi S Aboussouan, MD (2014-present)
Diane W Cox, PhD, FCCMG, FRSC; University of Alberta (2005-2014)
Felicitas L Lacbawan, MD (2014-present)
Kamilla Schlade-Bartusiak, PhD; University of Alberta (2005-2014)
James K Stoller, MD, MS (2014-present)

Revision History

  • 19 January 2017 (jks) Revision: clarification re serum levels of AAT in heterozygotes (Confirming the Diagnosis)
  • 1 May 2014 (me) Comprehensive update posted live
  • 6 February 2008 (cd) Revision: sequence analysis available on a clinical basis
  • 27 October 2006 (me) Review posted to live Web site
  • 15 February 2005 (dc) Original submission
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