Alpha-1 antitrypsin deficiency




Alpha 1-antitrypsin deficiency is a genetic disorder that causes defective production of alpha 1-antitrypsin (A1AT), leading to decreased A1AT activity in the blood and lungs, and deposition of excessive abnormal A1AT protein in liver cells. There are several forms and degrees of deficiency; the form and degree depend on whether the sufferer has one or two copies of the defective allele because it is a co-dominant trait. Severe A1AT deficiency causes panacinar emphysema or COPD in adult life in many people with the condition (especially if they are exposed to cigarette smoke). The disorder can lead to various liver diseases in a minority of children and adults, and occasionally more unusual problems. It is treated through avoidance of damaging inhalants and, in severe cases, by intravenous infusions of the A1AT protein or by transplantation of the liver or lungs. It usually produces some degree of disability and reduces life expectancy.


Symptoms of alpha-1 antitrypsin deficiency include shortness of breath, wheezing, rhonchi, and rales. The patient's symptoms may resemble recurrent respiratory infections or asthma that does not respond to treatment. Individuals with A1AD may develop emphysema during their thirties or forties even without a history of significant smoking, though smoking greatly increases the risk for emphysema. A1AD causes impaired liver function in some patients and may lead to cirrhosis and liver failure (15%). In newborns, alpha-1 antitrypsin deficiency has indicators that include early onset jaundice followed by prolonged jaundice. It is a leading indication for liver transplantation in newborns.

Associated conditions:

α1-antitrypsin deficiency has been associated with a number of diseases.


Alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the SERPINA1 gene. This gene gives the body instructions to make a protein called alpha-1 antitrypsin (AAT), which protects the body from an enzyme called neutrophil elastase. Neutrophil elastase helps the body fight infections, but it can also attack healthy tissues (especially the lungs) if not controlled by AAT.

Mutations that cause AAT can cause a deficiency or absence of AAT, or a form of AAT that does not work well. This allows neutrophil elastase to destroy lung tissue, causing lung disease. In addition, abnormal AAT can build up in the liver and cause damage to the liver.

The severity of AATD may also be worsened by environmental factors such as exposure to tobacco smoke, dust, and chemicals.

Serpin peptidase inhibitor, clade A, member 1 (SERPINA1) is the gene that encodes the protein Alpha 1-antitrypsin. SERPINA 1 has been localized to chromosome 14q32. Over 75 mutations of the SERPINA1 gene have been identified but clinically significant effects for Alpha 1-antitrypsin deficiency have only been attributed to a missense mutation in exon 5. The single base-pair substitution produces the allele "Z" which causes alpha 1-antitrypsin deficiency. The non-mutated SERPINA1 corresponds to the “M” allele which produces normal levels of alpha 1-antitrypsin. Genetic diagnosis of Alpha 1-antitrypsin deficiency is performed through polymerase chain reaction (PCR) of the localized mutated region of SERPINA1 or allele-specific oligonucleotides (ASO probes). A hybridized ASO probe containing the mutated sequence for the “Z” allele and an ASO probe bearing the normal DNA sequence allow direct determination of the individual's genotype, the identification of the “Z” allele in the individual and the genetic diagnosis of Alpha 1-antitrypsin deficiency.


Relatives of those with the deficiency are offered screening to establish whether they're carriers. If the abnormal gene is identified, couples who want to start a family are offered genetic counselling.


A1AT deficiency remains undiagnosed in many patients. Patients are usually labelled as having COPD without an underlying cause. It is estimated that about 1% of all COPD patients actually have A1AT deficiency. Thus, testing should be performed for all patients with COPD, asthma with irreversible air-flow obstruction, unexplainedliver disease, or necrotizing panniculitis. The initial test performed is serum A1AT level. A low level of A1AT confirms the diagnosis and further assessment with A1AT protein phenotyping and A1AT genotyping should be carried out subsequently.

As protein electrophoresis does not completely distinguish between A1AT and other minor proteins at the alpha-1 position (agarose gel), antitrypsin can be more directly and specifically measured using a nephelometric or immunoturbidimetric method. Thus, protein electrophoresis is useful for screening and identifying individuals likely to have a deficiency. A1AT is further analysed by isoelectric focusing (IEF) in the pH range 4.5-5.5, where the protein migrates in a gel according to its isoelectric point or charge in a pH gradient. Normal A1AT is termed M, as it is migrates toward the center of such an IEF gel. Other variants are less functional, and are termed A-L and N-Z, dependent on whether they run proximal or distal to the M band. The presence of deviant bands on IEF can signify the presence of alpha 1-antitrypsin deficiency. Since the number of identified mutations has exceeded the number of letters in the alphabet, subscripts have been added to most recent discoveries in this area, as in the Pittsburgh mutation described above. As every person has two copies of the A1AT gene, a heterozygote with two different copies of the gene may have two different bands showing on electrofocusing, although a heterozygote with one null mutant that abolishes expression of the gene will only show one band. In blood test results, the IEF results are notated as, e.g., PiMM, where Pi stands for protease inhibitor and "MM" is the banding pattern of that person.

Other detection methods include use of enzyme-linked-immuno-sorbent-assays in vitro and radial immunodiffusion. Alpha 1-antitrypsin levels in the blood depend on the genotype. Some mutant forms fail to fold properly and are, thus, targeted for destruction in the proteasome, whereas others have a tendency to polymerise, thereafter being retained in the endoplasmic reticulum. The serum levels of some of the common genotypes are:

  • PiMM: 100% (normal)
  • PiMS: 80% of normal serum level of A1AT
  • PiSS: 60% of normal serum level of A1AT
  • PiMZ: 60% of normal serum level of A1AT
  • PiSZ: 40% of normal serum level of A1AT
  • PiZZ: 10-15% (severe alpha 1-antitrypsin deficiency)

PiZ is caused by a glutamate to lysine mutation at position 342, while PiS is caused by a glutamate to valine mutation at position 264. Other rarer forms have been described; in all there are over 80 variants.


The outlook for most people with Alpha-1-antitrypsin deficiency is good – many won’t even know they have the condition while others can keep healthy with careful management. Although progressive liver or lung disease affects only a minority, it can be serious, so regular monitoring of those with the condition is important.


In the United States, Canada, and several European countries, lung-affected A1AD patients may receive intravenous infusions of alpha-1 antitrypsin, derived from donated human plasma. This augmentation therapy is thought to arrest the course of the disease and halt any further damage to the lungs. Long-term studies of the effectiveness of A1AT replacement therapy are not available. It is currently recommended that patients begin augmentation therapy only after the onset of emphysema symptoms.

To date (April 2015) there are four IV augmentation therapy manufacturers in the United States, Canada and several European countries. Intravenous (IV) therapies are the standard mode of augmentation therapy delivery. Researchers are exploring inhaled therapies. IV Augmentation therapy is manufactured by the following companies and have been shown to be clinically identical to one another in terms of dosage and efficacy.

  1. Grifols
  2. Baxter Theraputics
  3. CSL-Behring
  4. Kamada Ltd.

Augmentation therapy is not appropriate for liver-affected patients; treatment of A1AD-related liver damage focuses on alleviating the symptoms of the disease. In severe cases, liver transplantation may be necessary.

As α1-antitrypsin is an acute phase reactant, its transcription is markedly increased during inflammation elsewhere in response to increased interleukin-1 and 6 and TNFα production.

Treatments currently being studied include recombinant and inhaled forms of A1AT. Other experimental therapies are aimed at the prevention of polymer formation in the liver.


  • NIH