Back To Search Results

Alpha-1 Antitrypsin Mutation

Editor: Timothy J. Craig Updated: 9/26/2022 11:05:13 PM


Alpha-1 antitrypsin is a protease inhibitor produced primarily in the liver. It inhibits the neutrophil elastase activity in the lung and hence can protect it from proteolytic damage. It is responsible for approximately 90% of the protection against elastolytic activity in the lower airways caused by elastase released from neutrophils. If the neutrophils' elastases are not opposed, panacinar lung tissue is damaged and increases the risk of developing chronic obstructive pulmonary disease (COPD). On the other hand, the retention and accumulation of mutated polymers in the endoplasmic reticulum of hepatocytes renders the individuals with this disease at risk of "a gain of toxic function" leading to liver disease.[1][2][3]


Register For Free And Read The Full Article
Get the answers you need instantly with the StatPearls Clinical Decision Support tool. StatPearls spent the last decade developing the largest and most updated Point-of Care resource ever developed. Earn CME/CE by searching and reading articles.
  • Dropdown arrow Search engine and full access to all medical articles
  • Dropdown arrow 10 free questions in your specialty
  • Dropdown arrow Free CME/CE Activities
  • Dropdown arrow Free daily question in your email
  • Dropdown arrow Save favorite articles to your dashboard
  • Dropdown arrow Emails offering discounts

Learn more about a Subscription to StatPearls Point-of-Care


Genetic mutations, also known as serpinopathies, in the serpin superfamily cause alpha-1 antitrypsin deficiency. The condition is autosomal codominant, which consequently will make the affected individuals have a homozygous or heterozygous mutation in the SERPINA1 gene located on the long arm of chromosome 14. The standard nomenclature to describe alpha-1 antitrypsin deficiency uses an acronym for protease inhibitor (PI) along with the alleles that have been identified. The most common allele is associated with normal function of alpha-1 antitrypsin and is labeled M. PI*MM is the most common homozygous allele. The most common deficiency alleles are Z, and S. Uncommon deficiency alleles include I,  M, M, null, as well as other very rare ones. Polymerase chain reaction (PCR) techniques are used to detect specific DNA sequences that identify AAT alleles. The PI*Z allele, characterized by a single amino acid substitution of lysine for glutamic acid at position 342 on the 394 amino acid AAT molecule, is involved in approximately 95% to 96% of known clinical cases of severe AATD. Such amino acid substitution leads to polymerization of the abnormally formed protein in the hepatocyte and lowers inhibitory function to neutrophil elastases in the lungs. The PI*S allele, which involves the substitution of valine for glutamic acid at position 264, is associated with accelerated degradation in hepatocytes, but not with an increased risk for liver disease. The homozygous condition PI*SS is not associated with clinical lung disease, yet approximately 10% of double heterozygous PI*SZ can be at risk of COPD if the AAT levels were below the reference range, or if they were smokers.[4][5]


Studies have shown that the most commonly found deficiency allele in alpha-1 antitrypsin deficiency is the PI*Z allele that has a higher prevalence in northern and western Europe, while PI*S allele variants have a higher prevalence in southern Europe. The prevalence of the PI*ZZ deficiency allele accounts for 0.1% of the world population, while PI*SZ heterozygous allele deficiency represents about 0.7% of deficiency genotypes worldwide. Despite the relatively common appearance of these deficiency alleles, AATD is highly under-diagnosed, with fewer than 10% of the expected number of cases reported in the United States. The mean age when the disease was diagnosed was 41.3 years. As in other rare diseases, it often takes several doctors and many years before the diagnosis is made.[6][7]

History and Physical

Alpha-1 antitrypsin deficiency leads to COPD, liver disease, and panniculitis. Other studies have linked it to several other conditions such as glomerulonephritis and certain cancers. Other associations like celiac disease, fibromuscular dysplasia, and pancreatitis. There is also approximately 15% of patients with granulomatosis with polyangiitis who are found to have a ZZ genotype.

Pulmonary Disease

Pulmonary clinical manifestations are similar to the COPD of other etiologies; however, it has some certain characters such as early onset of symptoms, usually in the third or fourth decade and on CT the emphysematous involvement is mainly in the lung base. However, symptoms may not present until later, and the basilar changes may occur along with apical changes, thus making the symptoms or signs of ATTD similar to COPD unrelated to ATTD. Symptoms are mainly: dyspnea, cough, wheezing, and upper respiratory tract infections. The pulmonary symptoms can be aggravated by some risk factors like cigarette smoking, exposure to burning biomass materials, and respiratory infections. Such factors increase the unopposed elastase activity of neutrophils leading to the destruction of lung tissue and eventually COPD.

Extrapulmonary Manifestations

The accumulation of the ZZ protein and development of polymers leads to hepatitis in children, liver cirrhosis in adults, and increase the risk for hepatocellular carcinoma. Early in life infants may develop clinical hepatitis and AATD is the second most cause of liver transplant in children. As childhood continues liver inflammation subsides only to be replaced by smoldering inflammation in adults leading to cirrhosis in some, which in the majority of cases is subclinical. A small fraction of adults progress to liver failure and need a liver transplant. Panniculitis is a rare presentation of ZZ genotype and occurs in 1 per 1000 cases.


The American Thoracic Society and the European Respiratory Society have proposed that all patients with COPD, nonresponsive asthmatic adults, and adolescents, cryptogenic cirrhosis or liver disease without obvious etiology should be screened for alpha-1 antitrypsin deficiency using quantitative testing. Initial testing is through determining alpha one antitrypsin serum levels. If serum levels are low, genotyping may be pursued. If the genotype and serum level are discordant than phenotyping or genetic analysis can confirm the diagnosis. Chest radiographs and chest CT scan demonstrate emphysematous lung changes. Pulmonary function tests are necessary as well to detect the expected decline in FEV1.[8][9]

Treatment / Management

Individuals with alpha-1 antitrypsin deficiency should avoid triggers that stimulate the unopposed neutrophil elastase activity such as smoking and infections. Available vaccines that are important to prevent infections in patients are pneumococcal polysaccharide vaccine, yearly influenza vaccine, protein conjugate pneumococcal vaccine, and tetanus-diphtheria-pertussis vaccine. Inhalers typically used for COPD should be prescribed and initially should include long-acting beta-agonists (LABA) and or anticholinergics (LAMA). Because of the increased risk of pneumonia inhaled corticosteroids (ICS) should be reserved for when patients develop frequent exacerbations despite the other two inhalers. Pulmonary rehabilitation, oxygen, and in some circumstances, lung transplant, should be prescribed as indicated. Transplant is usually reserved for those that fall below an FEV-1 of 30% despite maximum therapy.

Augmentation Therapy

Augmentation therapy should not displace typical COPD therapies, but instead should be used to preserve lung function. Augmentation includes an infusion of purified pooled human plasma alpha antitrypsin which is infused IV weekly to increase and maintain serum alpha one antitrypsin levels near the threshold values, but definitely above the critical threshold of 11 micrometers or 57 mg/dl that is thought to be essential to preserve lung function. Augmentation therapy is only indicated for patients who have severe alpha one antitrypsin serum deficiency and COPD. Augmentation therapy is infused to elevate alpha one antitrypsin levels in plasma to oppose the elastase activity of the neutrophils in the lungs, which protects the lung tissue from damage. The benefit of augmentation seems to be best in patients with FEV-1 below 70%, and an FEV-1 above 30% and because of these data guidelines suggest using augmentation between these 2 FEV-1 values. Currently, the Food and Drug Administration (FDA) in the United States only approves augmentation therapy at doses of 60 mg/kg weekly. Adverse effects of augmentation therapy are rare and include a headache, nausea and dizziness and very rarely anaphylaxis. Augmentation does not affect liver disease.


The role of lung transplantation and its efficacy in alpha-1 antitrypsin deficiency patients is not yet established due to insufficient data. However, in 2013 the International Society for Heart and Lung Transplantation has reported that COPD related to alpha-1 antitrypsin deficiency accounted for the fourth highest percentage of lung transplants in the adult population between January 1995 and June 2012. A retrospective cohort study has shown that patients with alpha-1 antitrypsin deficiency who had bilateral lung transplantation have a faster rate of FEV1 decline compared to non-alpha-1 antitrypsin deficiency transplantation ones, yet there was a wide degree of similarity between both groups including post-transplant FEV1 slope, the severity of acute cellular rejection, and survival rate. On the other hand, survival times were shown to be significantly longer in those who had the transplant compared to those who did not believe in very severe COPD (FEV-1 below 30%). The limited data on lung volume reduction surgery have not been promising, and thus this procedure is not recommended for alpha one antitrypsin deficiency patients.   Following the liver transplant, it has not been established whether the new liver secreting normal alpha-1-protein will prevent the progression of lung disease. Unfortunately, for this reason, there is not a consensus if alpha-1-protein augmentation should be administered to patients after lung transplant.

Future of Alpha-1 Antitrypsin


Inhaled augmentation therapy

By inhalation, there is an opportunity to target treatment to the organ of interest, and hence reducing the required dose of alpha-1-protein necessary to preserve lung function. Inhaled therapy reduces the amount of alpha-1 protein needed, and this reduces the cost. Also, inhaled therapy reduces the need for intravenous therapy and multiple injections per month, as well as associated adverse events. Data supporting this route of therapy are lacking and until further studies are available intravenous therapy should be the preferred route of augmentation.

Gene therapy

The problem with augmentation therapy is that it is costly and requires weekly to monthly IV infusions, which carry a risk of allergic reactions and infections. Contrary, gene therapy offers the advantage of a single administration and if successful produces constant levels of alpha one antitrypsin. The strategy of gene therapy is to delivery the normal human M-type alpha one antitrypsin complementary DNA under control of a constitutive promoter using a gene transfer vector, and consequently, the transduced cells can secrete the deficient protein to the blood after a single administration. The parameters to be considered in gene therapy are the vector and the organ to be modified genetically and in which the gene will be expressed, and for these reasons, different approaches have been used.

Recombinant alpha-1 antitrypsin

Studies are underway to determine the effectiveness and safety of recombinant products to replace human plasma-derived alpha-1 protein. The progress thus far has been limited, but presently a humanized protein with 2 elastase inactivating sites is being studied.

Differential Diagnosis

  • Autoimmune hepatitis
  • Bronchiectasis
  • Bronchitis
  • Chronic obstructive pulmonary disease
  • Cystic fibrosis
  • Emphysema
  • Kartagener Syndrome
  • Viral hepatitis

Enhancing Healthcare Team Outcomes

Alpha-1 antitrypsin deficiency is a systemic disorder that affects many organs, thus it is best managed by an interprofessional team. Alpha-1 antitrypsin deficiency leads to COPD, liver disease, and panniculitis. Other studies have linked it to several other conditions such as glomerulonephritis and certain cancers. Other associations like celiac disease, fibromuscular dysplasia, and pancreatitis. There is also approximately 15% of patients with granulomatosis with polyangiitis who are found to have a ZZ genotype. The primary care provider and nurse practitioner should educate the patient on avoidance of triggers that stimulate the unopposed neutrophil elastase activity such as smoking and infections. Patients should be encouraged to get the yearly influenza vaccine, protein conjugate pneumococcal vaccine, and tetanus-diphtheria-pertussis vaccine. Inhalers typically used for COPD should be prescribed and initially should include long-acting beta-agonists (LABA) and or anticholinergics (LAMA). Because of the increased risk of pneumonia inhaled corticosteroids (ICS) should be reserved for when patients develop frequent exacerbations despite the other two inhalers. Pulmonary rehabilitation, oxygen, and in some circumstances, lung transplant, should be prescribed as indicated. Transplant is usually reserved for those that fall below an FEV-1 of 30% despite maximum therapy.



Felisbino MB,Fernandes FLA,Nucci MCNM,Pinto RMC,Pizzichini E,Cukier A, The patient profile of individuals with Alpha-1 antitrypsine gene mutations at a referral center in Brazil. Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia. 2018 Sep-Oct;     [PubMed PMID: 30517339]


Foil KE,Blanton MG,Sanders C,Kim J,Al Ashry HS,Kumbhare S,Strange C, Sequencing Alpha-1 MZ Individuals Shows Frequent Biallelic Mutations. Pulmonary medicine. 2018;     [PubMed PMID: 30254761]


Greulich T,Rodríguez-Frias F,Belmonte I,Klemmer A,Vogelmeier CF,Miravitlles M, Real world evaluation of a novel lateral flow assay (AlphaKit® QuickScreen) for the detection of alpha-1-antitrypsin deficiency. Respiratory research. 2018 Aug 13;     [PubMed PMID: 30103740]


Comba A,Demirbaş F,Çaltepe G,Eren E,Kalayci AG, Retrospective analysis of children with α-1 antitrypsin deficiency. European journal of gastroenterology     [PubMed PMID: 29505478]

Level 2 (mid-level) evidence


Esquinas C,Janciauskiene S,Gonzalo R,Mas de Xaxars G,Olejnicka B,Belmonte I,Barrecheguren M,Rodriguez E,Nuñez A,Rodriguez-Frias F,Miravitlles M, Gene and miRNA expression profiles in PBMCs from patients with severe and mild emphysema and PiZZ alpha1-antitrypsin deficiency. International journal of chronic obstructive pulmonary disease. 2017;     [PubMed PMID: 29238183]


Ferreira TCDS,Queiroz MAF,Argañaraz GA,Ishak R,Vallinoto ACR,Argañaraz ER, A1AT polymorphisms may be associated with clinical characteristics of retrovirus infections in a mixed ethnic population from the Brazilian Amazon region. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. 2017 Dec;     [PubMed PMID: 29030134]


Teckman JH, Emerging Concepts and Human Trials in Alpha-1-Antitrypsin Deficiency Liver Disease. Seminars in liver disease. 2017 May;     [PubMed PMID: 28564723]


Belmonte I,Montoto L,Rodríguez-Frías F, Laboratory Diagnosis by Genotyping. Methods in molecular biology (Clifton, N.J.). 2017;     [PubMed PMID: 28752445]


Marciniak SJ,Ordóñez A,Dickens JA,Chambers JE,Patel V,Dominicus CS,Malzer E, New Concepts in Alpha-1 Antitrypsin Deficiency Disease Mechanisms. Annals of the American Thoracic Society. 2016 Aug;     [PubMed PMID: 27564663]