When your infant or young child show signs of liver disease; when you develop emphysema before age 40; when you have chronic obstructive pulmonary disease (COPD) or unexplained liver disease at any age; when you have a close relative with alpha-1 antitrypsin deficiency
A blood sample drawn from a vein in your arm
Alpha-1 antitrypsin (AAT) is a protein in the blood that protects the lungs from damage caused by activated enzymes. Laboratory tests measure the level of AAT in blood or identify abnormal forms of AAT that a person has inherited to help diagnose alpha-1 antitrypsin deficiency.
AAT helps to inactivate several enzymes, the most important of which is elastase. Elastase is an enzyme produced by white blood cells called neutrophils and 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. If its action is not regulated by AAT, elastase will also begin to break down and damage lung tissue.
Each individual inherits two copies of the gene that codes for AAT. It is called the protease inhibitor (SERPINA1) gene. This gene is co-dominant, which means that each SERPINA1 gene copy is responsible for producing half of the body's AAT. If there is a change or mutation in one or both of the gene copies, then less AAT and/or AAT with reduced function is produced.
When AAT production drops below 30% of normal, the affected person will experience a disorder called alpha-1 antitrypsin deficiency. People 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.
Certain types of dysfunctional AAT accumulate in the liver cells, where it is produced. As AAT builds up in these cells, it forms abnormal protein chains and begins to destroy the cells and damage the liver. About 10% of newborns with AAT deficiency have liver damage and are jaundiced. In severe cases, these infants may require a liver transplant to survive. AAT deficiency is currently the most common genetic cause of liver disease in the pediatric population.
In adults with AAT deficiency, the risk of developing chronic liver disease, cirrhosis, and liver cancer (hepatocellular carcinoma) is increased. Few adults with AAT deficiency actually have signs or symptoms of liver disease, however. The amount and function of the AAT depends on the gene mutation that is inherited. While there are more than 120 different alleles in the SERPINA1 gene, only a few are common. Most people in the U.S., about 90%, have two copies of the normal "wild type" M gene (MM). The most common abnormal genes are labeled S and Z.
How is it used?
Alpha-1 antitrypsin (AAT) testing is used to help diagnose alpha-1 antitrypsin deficiency as the cause of early onset emphysema or chronic obstructive pulmonary disease (COPD) when a person does not have obvious risk factors such as smoking or exposure to lung irritants such as dust and fumes. It may also be used when someone has asthma that obstructs his or her breathing, even after treatment.
Testing is also used to help diagnose the cause of persistent jaundice and other signs of unexplained liver injury. This is done primarily in infants and young children but may be done in people of any age.
Testing may also be used to help determine whether a person who has a family history of alpha-1 antitrypsin deficiency has one or two copies of the SERPINA1 gene.
Three types of AAT tests are commonly available. One or more of these may be used to evaluate an individual:
- Alpha-1 antitrypsin measures the level of the protein AAT in blood.
- Alpha-1 antitrypsin phenotype testing evaluates the amount and type of AAT being produced and compares it to normal patterns.
- Alpha-1 antitrypsin genotype testing (DNA testing) can be used to establish which SERPINA1 gene alleles are present, including the normal wild type M allele or variant alleles. This test does not identify every variant, but it will detect the most common ones (S and Z) as well as variants that may be common in a particular geographical area or family. Once the affected person's SERPINA1 gene alleles have been identified, other family members may be tested to establish their own risk of developing emphysema and/or liver involvement as well as the likelihood that their children might inherit the disease.
Gene sequencing is uncommon for AAT but may be necessary to identify rare alleles and obtain an accurate diagnosis.
When is it ordered?
Alpha-1 antitrypsin testing may be ordered when:
- An infant has jaundice that lasts for more than a week or two, an enlarged spleen, fluid accumulation in the abdomen (ascites), persistent itching (pruritus), and other signs of liver injury
- Someone of any age has COPD, raised, tender skin spots that form ulcers (necrotizing panniculitis), a vascular disease called granulomatosis with polyangiitis, or unexplained airway widening (bronchiectasis)
- A person younger than 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 person 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.
- Someone has a close relative with alpha-1 antitrypsin deficiency
- An individual has an affected family member and wants to know the likelihood of having an affected child
In their 2003 guidelines, the American Thoracic Society recommends AAT testing when individuals are diagnosed with certain conditions such as:
- Emphysema at a young age (younger than 45 years old) and/or no obvious risk factors for the disease, such as smoking
- Asthma that is difficult to treat
- Liver disease with no known cause
- Necrotizing panniculitis
In their 2016 guidelines, intended to update the American Thoracic Society's guidelines, the Alpha-1 Foundation recommends AAT testing for all individuals with:
- Liver disease with no known cause
- Necrotizing panniculitis
- Granulomatosis with polyangiitis
- Unexplained bronchiectasis
What does the test result mean?
A low level of AAT in blood indicates that the person tested may have alpha-1 antitrypsin deficiency. The lower the level of AAT, the greater the risk of developing emphysema and other disorders related to AAT deficiency.
In people with an abnormal form of AAT, the risk of developing disease depends on how much is produced and which variant is present. A variant with very low activity may lead to both emphysema (because it does not protect the lungs) and liver disease (because of the buildup of abnormal AAT inside liver cells).
When DNA testing indicates the presence of one or two abnormal copies of the SERPINA1 gene, less AAT and/or abnormal AAT will be produced. The degree of AAT deficiency and the degree of lung and/or liver damage can vary greatly. Two people with the same abnormal genes may have very different disease courses. As with any genetic testing, a genetic counselor can explain the likelihood that the disease may be passed on to the affected person's children.
People with one copy of M and one of S or Z (MS or MZ) will produce reduced amounts of AAT but should have enough to protect themselves. They will be carriers of the condition, however, and can pass it on to their children.
Individuals with two copies of S (SS) may be asymptomatic or moderately affected (they produce about 60% of normal AAT).
People with one copy of S and one of Z (SZ) are at an increased risk of developing emphysema (they produce about 40% of normal AAT).
Individuals who have two copies of Z (ZZ) are the most severely affected (they only produce about 10% of the required AAT) along with those who have one or two copies of rare forms of the SERPINA1 gene that are "null" (they do not produce any AAT).
Is there anything else I should know?
AAT 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 AAT may also be seen with oral contraceptive use, pregnancy, and stress. These temporary or chronic AAT increases may cause levels to appear normal in people with mild to moderate AAT deficiency.
Protein electrophoresis is a test that evaluates many different proteins in the blood. Sometimes the test will detect a deficiency in AAT unexpectedly, when it is done for a different purpose. In those cases, follow-up testing for AAT may confirm a deficiency of the protein, even if there are no signs or symptoms of disease.
What can I do to take care of myself if I have alpha-1 antitrypsin (AAT) deficiency?
Don’t smoke. Taking care of your lungs can increase your lifespan and delay the onset of emphysema. Avoid lung irritants such as dust and fumes, get regular vaccinations to protect against pneumococcal pneumonia and Haemophilus influenzae type b infections, for example, and an annual influenza shot, get prompt medical attention for lung infections, and get regular exercise to help maintain lung function. Work with your healthcare practitioner to determine what steps will help you take care of yourself.
How common is alpha-1 antitrypsin deficiency?
It is thought to be one of the most frequent genetic deficiencies in Caucasians. The American Lung Association estimates that as many as 100,000 people in the U.S. are born with AAT deficiency each year and that as many as 25 million Americans are carriers of at least one deficient gene. AAT is an under diagnosed condition. About only 10% of severely deficient individuals have been identified.
Do I need to have all three types of AAT testing?