Alpha 1 Antitrypsin Mutation


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]


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]

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.

Article Details

Article Author

Ali Abdulkarim

Article Editor:

Timothy Craig


7/15/2020 8:01:19 AM



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,Demirba┼č F,Çaltepe G,Eren E,Kalayci AG, Retrospective analysis of children with ╬▒-1 antitrypsin deficiency. European journal of gastroenterology     [PubMed PMID: 29505478]


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]