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What is being tested?

Alpha-1-antitrypsin (A1AT) is a protein that is produced in the liver and released into the bloodstream. A1AT works by inactivating several enzymes but primarily the enzyme elastase in the lungs. Elastase is an enzyme produced by neutrophils (a type of white blood cell) and it is part of the body’s normal response to injury and inflammation. Elastase breaks down proteins so that they can be removed and recycled by the body but, if its action is not regulated by A1AT, elastase will also begin to break down and damage lung tissue.

A1AT is the product of the SERPINA1 gene, commonly known as the protease inhibitor (Pi) gene, of which everyone has two copies. Each Pi gene copy is responsible for producing half of the body's A1AT. If there is a change (called a 'mutation') in one or both of the gene copies, then less A1AT and/or A1AT that does not work properly, is produced. If the resulting A1AT production drops down to 30% of normal or less, then the affected patient will experience a disorder called alpha-1-antitrypsin deficiency. Patients with this disorder are at a considerable risk of developing emphysema (a progressive lung disease) in early adulthood. If they smoke, or are exposed to occupational dust or fumes, the lung damage tends to occur sooner and be more severe.

If the A1AT produced does not work properly it tends to accumulate in the liver cells that produce it. As it builds up in these cells, the A1AT forms abnormal protein chains and begins to destroy the cells and damage the liver. About 10% of those affected with A1AT deficiency will have liver disease as a newborn. Many improve on their own but in severe cases these infants may require a liver transplant to survive. A1AT deficiency is currently one of the most common reasons for a liver transplant in the paediatric population.

The amount and function of the A1AT created depends on the mutation inherited. While there are more than 70 different variations (alleles) in the Pi gene, only a few are common. Most people in Australia, about 90%, have two copies of the normal M gene (MM). The most common of the abnormal forms are S and Z. Those people with:

  • One copy of M and one of S or Z (MS or MZ) will produce reduced amounts of A1AT but should have enough to protect themselves. They will be carriers of the condition, however, and can pass it on to their children
  • Two copies of S (SS) may have no symptoms or be moderately affected (they produce about 60% of the required A1AT)
  • One copy of S and one of Z (SZ) are at an increased risk of developing emphysema (they produce only about 40% of normal A1AT)
  • Two copies of Z (ZZ) are the most severely affected (they only produce about 10% of the required A1AT) along with those who have one or two copies of rare forms of the Pi gene which are 'null' (they do not produce any A1AT)

Types of A1AT tests

  • Different A1AT tests can be used to measure the amount of A1AT, determine which types and concentrations of A1AT protein are present, and determine which Pi gene alleles a patient has.
  • Alpha-1-antitrypsin, this test measures the total amount of A1AT present
  • Alpha-1-antitrypsin phenotype, separates out the different variants of A1AT protein being produced and compares them to known patterns. It also allows an estimation of the amount of each type present. A protein electrophoresis test is sometimes used to screen for a severe A1AT deficiency
  • Alpha-1-antitrypsin DNA testing, genetic testing that can be done to identify which protease inhibitor gene mutations (Pi gene alleles) are present. Only the most common mutations are usually tested (M, S, Z). This test can be used to help evaluate affected patients and their family members

Doctors also occasionally test for the level of A1AT in the faeces (bowel motion). This is done when the doctor suspects the person is losing protein from the gastrointestinal tract and is NOT part of testing for alpha-1-antitrypsin deficiency.

How is it used?

An alpha-1-antitrypsin (A1AT) level is requested to help diagnose the cause of early onset emphysema, especially when a person does not have obvious risk factors such as smoking or exposure to lung irritants such as dust and fumes.

An A1AT level is also requested to help diagnose the cause of persistent jaundice and other signs of liver disease. This is done primarily in infants and young children but may also be done in patients of any age.

Alpha-1-antitrypsin phenotype testing may be requested if the A1AT level is lower than normal. It looks at the amount and type of A1AT being produced and compares it to normal patterns.

DNA testing may be done as a follow-up to an alpha-1-antitrypsin level and phenotype. Once it has been established that an abnormality exists, DNA genetic testing can be used to establish which Pi gene alleles are present. This test does not test for every variant, just the most common ones (M, S, and Z, as well as any that may be common in a particular geographical area or family). Once the affected person’s Pi gene alleles have been determined, other family members may be tested to establish their own possible risk of developing emphysema and/or liver disease, as well as the likelihood that their children might inherit it.

When is it requested?

Alpha-1-antitrypsin testing may be requested when a newborn or infant has jaundice that lasts for an extended period of time (more than a week or two), an enlarged spleen, ascites (fluid accumulation in the abdominal cavity), pruritus (itching), and other signs of liver injury. It may be ordered when a person under 40 years of age develops wheezing, a chronic cough or bronchitis, is short of breath after exertion and/or shows other signs of emphysema. This is especially true when the patient is not a smoker, has not been exposed to known lung irritants, and when the lung damage appears to be located low in the lungs. A1AT testing may also be done when you have a close relative with alpha-1-antitrypsin deficiency.

Alpha-1-antitrypsin phenotype testing is requested when a patient has a decreased level of A1AT. DNA testing is performed when the A1AT test indicates that the patient has a lower than normal level of A1AT and when the alpha-1-antitrypsin phenotype test shows that some or all of the A1AT protein being produced appears to be a variant. It may also be ordered in the rare case when no A1AT is being produced. A1AT DNA testing may be done on close relatives when there is an affected family member and when a patient wants to determine their risk of having an affected child.

What does the result mean?

A1AT concentrations are primarily important when they are lower than normal and/or indicate that the A1AT being produced is abnormal. The lower the level of normal A1AT, the greater the risk of developing emphysema.

With abnormal A1AT it depends on how much is produced and how abnormal it is. Low concentrations of abnormal A1AT in the blood may lead to both emphysema (because of the lack of lung protection) and to liver disease (because of the build-up of dysfunctional A1AT inside the liver cells producing it).

When DNA testing indicates the presence of one or two abnormal copies of the Pi gene, less A1AT and/or abnormal A1AT will be produced and the variant copies can be passed on to the patient’s children. The degree of A1AT deficiency and the degree of lung and/or liver damage experienced is very variable. Two people with the same gene copies may have very different disease courses.

Is there anything else I should know?

A1AT is an acute phase reactant. This means that it will be elevated in acute and chronic inflammatory conditions, infections, and with some cancers. Increased levels of A1AT may also be seen in pregnancy, stress and thyroid infections, and in patients taking oral contraceptives. This may cause levels to appear ‘normal’ in persons with mild to moderate A1AT deficiency when they also have another condition that increases A1AT.

A1AT concentrations may be decreased with neonatal respiratory distress syndrome, and with conditions that decrease serum proteins such as kidney disease (nephrotic syndrome), malnutrition and some cancers.

Common questions

  • What can I do to take care of myself if I have alpha-1-antitrypsin deficiency?

Don't smoke. Stopping smoking can increase your lifespan and delay the onset of emphysema. Take care of your lungs – avoid lung irritants such as dust and fumes, get an annual flu vaccine, get prompt medical attention for lung infections and get regular exercise to help maintain lung function.

  • How common is alpha-1-antitrypsin deficiency?

It is thought to be one of the most frequent genetic deficiencies in Caucasians. In Australia approximately 1 in 2500 have a significant degree of A1AT deficiency.

  • Can alpha-1-antitrypsin deficiency cause problems other than lung and liver disease?

Yes, the accumulation of abnormal alpha-1-antitrypsin protein may cause inflammation elsewhere in the body, such as a skin condition called panniculitis.

Last Updated: Thursday, 1st June 2023

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