Alpha-1-antitrypsin deficiency

Diagnosis and Testing

How do I get tested for alpha-1 antitrypsin deficiency?

You can get tested for alpha-1 antitrypsin deficiency (AATD) in different ways. A diagnosis can be made by measuring the level of the alpha-1 antitrypsin (AAT) protein in someone's blood. In people with AATD, this is much lower than usual. Specialized testing, called biochemical testing or PI typing, looks at the AAT protein forms in detail to determine if someone has AATD. Genetic testing can also study the sequence (spelling) of the DNA that make up the SERPINA1 gene, which is associated with AATD. This can find about 95% of people with AATD. People with AATD have two mutations in the SERPINA1 gene, one in each of their gene copies. Genetic testing can also find AATD carriers, who only have a mutation in one copy of their SERPINA1 genes.

Medical recommendations have been made about who should be tested for AATD, which include:

  • Anyone with chronic obstructive pulmonary disease (COPD), regardless of age or ethnic background
  • Anyone with unexplained chronic liver disease
  • Anyone with nectrotizing panniculitis, granulomatosis with polyangiitis, or unexplained bronchiectasis (all can be complications of AATD)
  • Following genetic counseling, parents/siblings/children/extended family of anyone found to have a SERPINA1 gene mutation

If you want to learn whether genetic testing for AATD may be right for you or your family member, speak to your healthcare provider about a referral to see a genetic counselor near you. In the U.S., the Alpha-1 Foundation provides free telephone-based genetic counseling and you can reach this service by calling 1-800-785-3177. Genetic counselors can be found on the National Society of Genetic Counselors website.

As of 2017, the Alpha-1 Foundation and Medical University of South Carolina also make free and confidential testing available for alpha-1 antitrypsin deficiency. This free testing is part of a research study called the Alpha-1 Coded Testing (ACT) Study. Participants receive a free, at-home test kit after completing an informed consent form and research questionnaire. Results are returned directly to the participant several weeks later. For more information, or to join the ACT Study for a free test kit, visit www.alphaoneregistry.org.

References
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More Diagnosis and Testing Content

Is there newborn testing for alpha-1 antitrypsin deficiency?

Is there more than one test for alpha-1 antitrypsin deficiency?

Are there different types of alpha-1 antitrypsin deficiency?

What does it mean to have inherited a "variant" or "variant of unknown significance" in the gene for alpha-1 antitrypsin deficiency?

What does my AAT level mean in alpha-1 antitrypsin deficiency?

What is a Pi type for alpha-1 antitrypsin deficiency?

How can I get tested for alpha-1 antitrypsin deficiency?

What does testing for alpha-1 antitrypsin deficiency involve?

How do I know if I have chronic obstructive pulmonary disease caused by alpha-1 antitrypsin deficiency?

What tests are performed to see if the liver is affected by alpha-1 antitrypsin deficiency?

Is there routine newborn screening for alpha-1 antitrypsin deficiency?

Is prenatal genetic testing possible for alpha-1 antitrypsin deficiency?

What are null mutations in the SERPINA1 gene for AATD?

What are the different mutations for alpha-1 antitrypsin deficiency?

How many genetic forms of alpha-1 antitrypsin deficiency are there?

Who should be tested for alpha-1 antitrypsin deficiency?

Is screening for alpha-1 antitrypsin deficiency possible during pregnancy?

Is there free genetic testing for alpha-1 antitrypsin deficiency?

Is there newborn testing for alpha-1 antitrypsin deficiency?

As of 2017, newborn testing/screening is not available in the U.S. for alpha-1 antitrypsin deficiency (AATD). Talk with your healthcare provider if there is a reason, such as family history or symptoms, that you would like to consider testing your newborn for AATD.

References
Is there more than one test for alpha-1 antitrypsin deficiency?

Testing for alpha-1 antitrypsin deficiency (AATD) can happen in different ways. A diagnosis can be made by measuring the level of the alpha-1 antitrypsin (AAT) protein in someone's blood. In people with AATD, this is much lower than usual. Specialized testing, called biochemical testing or PI typing, looks at the AAT protein forms in detail to determine if someone has AATD. Genetic testing at genetic testing laboratories can also study the sequence (spelling) of the DNA that make up the SERPINA1 gene, which is associated with AATD. This can find about 95% of people with AATD. People with AATD have two mutations in the SERPINA1 gene, one in each of their gene copies. Genetic testing can also find AATD carriers, who only have a mutation in one copy of their SERPINA1 genes.

If you want to learn whether genetic testing for AATD may be right for you or your family member, speak to your healthcare provider about a referral to see a genetic counselor near you. In the U.S., the Alpha-1 Foundation provides free telephone-based genetic counseling and you can reach this service by calling 1-800-785-3177. Genetic counselors can be found on the National Society of Genetic Counselors website.

The Alpha-1 Foundation and Medical University of South Carolina also make free and confidential testing available for alpha-1 antitrypsin deficiency. This free testing is part of a research study called the Alpha-1 Coded Testing (ACT) Study. Participants receive a free, at-home test kit after completing an informed consent form and research questionnaire. Results are returned directly to the participant several weeks later. For more information, or to join the ACT Study for a free test kit, visit www.alphaoneregistry.org.

References
Are there different types of alpha-1 antitrypsin deficiency?

Everyone with alpha-1 antitrypsin deficiency (AATD) has mutations in the gene called SERPINA1, but different mutations in the gene lead to different forms of AATD. For example, some mutations cause an increased risk for liver disease and others do not. The combination of mutations also determine how high the risk is for lung disease.

The SERPINA1 gene normally makes a protein called alpha-1 antitrypsin (AAT). AAT is a type of protein called a protease inhibitor (Pi). Normal AAT is called "M" (Pi M). Mutations in the SERPINA1 gene are named according to their abnormal AAT product. The "Z" mutation makes an abnormal AAT protein called "Z" (Pi Z). ZZ (PiZZ) alpha-1 is the most common form of AATD that is clinically diagnosed and people with this have the most severe symptoms. This happens when someone has two "Z" mutations.

References
What does it mean to have inherited a "variant" or "variant of unknown significance" in the gene for alpha-1 antitrypsin deficiency?

A variant of unknown significance (VUS) means that, from genetic testing, there is a change in spelling of the DNA in your SERPINA1 gene. This is the gene associated with alpha-1 antitrypsin deficiency (AATD). However, but it is not known yet whether that DNA variant causes AATD in people or not. Some DNA variants are harmless and do not cause disease, such as those that cause eye color or hair color changes. If you have been found to have a VUS from genetic testing, check back with your doctor or genetic counselor later to see if more information becomes known. As DNA variants are better understood over time and scientists find more people with them, your variant may be reclassified and your result may have a clearer meaning.

References
What does my AAT level mean in alpha-1 antitrypsin deficiency?

Your AAT level, or estimated AAT level, is the amount of alpha-1 antitrypsin protein in your blood. Alpha-1 antitrypsin deficiency (AATD) is classically defined as having an AAT level lower than 57 mg/dL or 11uM; however, there are variant forms where someone's AAT level may actually be higher, but it is not working well. AAT is an acute phase reactant protein, which means the levels tends to go up when the body has inflammation, infection, or during a pregnancy. It is normal for someone's AAT level to vary within the range for their genetic type of AATD. In most cases, you shouldn't need to have regular AAT level measurements taken. An AAT level alone is not enough to confirm if someone is an AATD carrier. In those situations, genetic testing is needed.

References
What is a Pi type for alpha-1 antitrypsin deficiency?

Pi stands for protease inhibitor. Alpha-1 antitrypsin is a type of protein called a protease inhibitor, so Pi type is the type(s) of alpha-1 protein that your body (primarily in your liver) makes. A Pi type is represented by two letters (such as MM, MZ, MS, ZZ). A Pi type is determined by a laboratory method called isoelectric focusing. In most cases your Pi type and your genetic type are the same. You can ask your doctor, genetic counselor, or contact the Alpha-1 Foundation's genetic counselor at 1-800-785-3177 if you have questions about finding out your Pi type or what your Pi type means. Genetic counselors can be found on the National Society of Genetic Counselors website.

References
How can I get tested for alpha-1 antitrypsin deficiency?

You can ask your doctor or genetic counselor to order genetic testing for alpha-1 antitrypsin deficiency (AATD). You can find a genetic counselor near you in the U.S. by using the Find a Genetic Counselor search tool on the National Society of Genetic Counselors' website. The Alpha-1 Foundation also has a genetic counselor who can help understand your testing options and results. This is a free and confidential service in the U.S. Call 1-800-785-3177 to speak with the alpha-1 genetic counselor.

As of 2017, the Alpha-1 Foundation and Medical University of South Carolina also make free and confidential testing available for alpha-1 antitrypsin deficiency. This free testing is part of a research study called the Alpha-1 Coded Testing (ACT) Study. Participants receive a free, at-home test kit after completing an informed consent form and research questionnaire. Results are returned directly to the participant several weeks later. For more information, or to join the ACT Study for a free test kit, visit www.alphaoneregistry.org.

References
What does testing for alpha-1 antitrypsin deficiency involve?

Only blood testing can determine if someone has alpha-1 antitrypsin deficiency (AATD). A medical exam alone cannot determine whether someone has AATD. Additionally, some people who have changes, or mutations, in the gene for AATD (called SERPINA1) stay healthy for some or all of their lives. Genetic testing requires a blood sample, which may be taken by a finger stick or by a standard blood draw. The laboratory will do one or more of the following tests on your blood sample:

  • Immunoassay (AAT Level). This measures the amount of alpha-1 protein in your blood. This indicates if you have a normal, intermediate, or very low amount of alpha-1 circulating in your blood.
  • Phenotyping. This is a protein typing test. This test determines the types of proteins in your blood. This result is in the form of two letters. M (normal) would mean that only M protein was detected. MZ (carrier) would mean both M and Z were detected. Z (abnormal) would mean only Z was detected. Because the proteins produced are determined by genes, protein types correspond with gene types (genotype) in most cases. There are many possible phenotyping results that correspond with the 150+ gene types for alpha-1.
  • Genotyping. This test looks for specific mutations in your SERPINA1 gene. Genotyping always looks for the most common mutation, called "Z." Some genotyping tests look for additional mutations, such as S, F, I and others. Genotype results are usually given as two letters (such as MM, MZ, ZZ). Each letter indicates an inherited code for how your body will produce AAT. Anyone reviewing results should be cautious, as a normal M allele is often reported if other mutations (a limited number) looked for are not seen. Therefore, someone may still have a risk for rare mutations, especially if there are known rare mutations in the family.
  • Gene Sequencing. This test is more detailed than genotyping and can find very rare changes in the SERPINA1 gene. This testing may be offered if an unusual result is found on earlier testing, or if a SERPINA1 gene mutation is already known to be in the family.

The above tests can determine whether you inherited AATD, which is a genetic predisposition to lung and liver disease. Additional medical tests with your doctor are needed to determine whether you actually have lung or liver disease. Most people with AATD do not have symptoms for much of their life, despite being born with the condition.

References
How do I know if I have chronic obstructive pulmonary disease caused by alpha-1 antitrypsin deficiency?

The following testing may be performed to help diagnose chronic obstructive pulmonary disease:

  • Spirometry: A breathing test called spirometry (also called a pulmonary function test or PFT) is needed to diagnose chronic obstructive pulmonary disease (or COPD). This pain-free test measures your lung function using a device called a spirometer. You breathe out into a mouthpiece, and the spirometer measures the amount of air and the speed of air you blow out.
  • Chest imaging: A chest x-ray makes a picture of your heart and lungs. It can be used to rule out other lung problems and can find some signs in the lungs of COPD. A chest x-ray alone cannot diagnose COPD, but it can offer your doctor important information. A chest computed tomography (or CT) test is similar to an x-ray, and may be done to better see the extent of emphysema in your lungs. Emphysema is one component of COPD and also common in alpha-1 antitrypsin deficiency (AATD).
  • Pulse oximeter: Your doctor may also measure the level of oxygen in your blood with a simple device called a pulse oximeter, which painlessly clips to your finger.
References
What tests are performed to see if the liver is affected by alpha-1 antitrypsin deficiency?

Signs of liver disease will be looked for patients with alpha-1 antitrypsin deficiency:

  • Your doctor will look for signs of liver disease, such as jaundice (yellowing of the skin), swollen or tender belly, or an enlarged or firm liver or spleen. Sometimes liver disease does not cause obvious signs.
  • Blood tests: Blood tests can measure liver enzymes. When the liver is damaged, these enzymes are elevated.
  • Liver ultrasound: This test uses sound waves through the skin to make a picture of the liver, which can show signs of liver disease.
References
Is there routine newborn screening for alpha-1 antitrypsin deficiency?

As of May 2019, alpha-1 antitrypsin deficiency (AATD) is not currently a condition on routine newborn screening tests in the U.S. Talk with your healthcare provider if there is a reason, such as family history or symptoms, that you would like to consider testing your newborn for AATD.

References
Is prenatal genetic testing possible for alpha-1 antitrypsin deficiency?

Prenatal diagnosis (genetic testing) by the amniocentesis or chorionic villus sampling (CVS) procedures is possible for alpha-1 antitrypsin deficiency (AATD). This can happen when the parents of the baby have had genetic testing and their SERPINA1 gene mutations are known, which means the baby is known to be at risk for AATD. Anyone interpreting abnormal prenatal genetic results should be cautious, because abnormal genetic results cannot usually predict how mild or severe the AATD will be in the baby or child. One exception is that babies with the ZZ genetic makeup, who have had a sibling with severe liver disease and the same ZZ gene makeup, have a higher risk to also have severe liver disease.

References
What are null mutations in the SERPINA1 gene for AATD?

There are many different mutations in the SERPINA1 gene, which is associated with alpha-1 antitrypsin deficiency (AATD). Null mutations result in no alpha-1 antitrypsin (AAT) protein being produced. Null mutations result in great reduction of AAT in the blood and an increased risk for lung disease. Null mutations do not raise the risk for liver disease. Sequencing of the SERPINA1 gene by genetic testing is needed to fully define null mutations in each situation.

References
What are the different mutations for alpha-1 antitrypsin deficiency?

All mutations for alpha-1 antitrypsin deficiency (AATD) occur in the SERPINA1 gene. A person's risk for symptoms of AATD depends on both copies of their SERPINA1 gene.

  • Z: This mutation produces an abnormal alpha-1 antrityps (AAT) protein that gets trapped in the liver and reduces the quantity of AAT in the blood. Having two Z mutations raises the risk for both lung and liver disease.
  • S: This mutation results in a moderately reduced quantity of AAT protein in the blood. Having the S mutation is not typically associated with liver disease.
  • I: This mutation results in a reduced quantity of AAT protein in the blood. Based on a limited amount of information, it is not known to be associated with liver disease.
  • F: This mutation produces a normal or near-normal quantity of AAT protein, but the AAT does not work properly. The F mutation raises the risk for AATD-lung disease and is not known to be associated with liver disease. An AAT level alone will not detect AATD involving the F genetic type. A genotyping or phenotyping test with targeted detection of the F mutation is needed for this.
  • Null: This category includes many different mutations in the SERPINA1 gene. Null mutations result in no AAT protein being made. This results in a great reduction of AAT amount in the blood and an increased risk for lung disease. Null mutations do not raise the risk for liver disease. SERPINA1 gene sequencing is needed to fully define null mutations in each case.

There are many other rare mutations in the SERPINA1 gene. In the U.S., call the Alpha-1 Foundation genetic counselor (1-800-785-3177) if you have questions about the SERPINA1 mutation or mutations in your family.

References
How many genetic forms of alpha-1 antitrypsin deficiency are there?

Alpha-1 antitrypsin deficiency (AATD) has many genetic forms:

MM: This is the normal alpha-1 antitrypsin deficiency genotype. About 92% of Caucasians are genotype MM. Individuals with MM have no increased risk for AATD-related disorders and no increased risk to relatives.

MZ, MS, M-Other: These are AATD carriers and they may have a mild deficiency. All parents, children, and full siblings of AATD carriers also have a 50% risk to be carriers. Genetic testing should be considered for these family members. Based on family or medical history, some people in the family may have an increased risk for severe AATD.

SS: This genotype is associated with an intermediate alpha-1 antitrypsin protein levels. A person's risk for lung disease may be mildly increased and smoking should be avoided. Risks for liver disease are not increased.

SZ: This genotype causes a moderate to severe deficiency of alpha-1 antitrypsin protein levels and an increased risk for AATD-related lung disease. Risk for liver disease is somewhat increased. Your specific risks and symptoms should always be discussed with a trained medical professional. See http://alpha-1foundation.org/clinical-resource-centers/ to find a specialist near you.

Your parents and children are "obligate carriers" of either the S or the Z. Carriers may wish to know this for lifestyle planning, healthcare management and reproductive decision making. Testing should be considered. Risk for a given individual to be more severely affected depends on the genotypes of both of their parents. It uncommon for multiple generations of a family to be severely affected (SZ, ZZ), though this can occur.

Your full siblings are at-risk to have the SZ genotype, as well. They may also be Alpha-1 carriers or unaffected and not a carrier. Testing is recommended.

ZZ: This genotype causes a severe deficiency and significantly increased risk for alpha-1 lung disease in adults. Risk for liver disease is also increased in infants and adults. Severe liver disease affects a small portion of infants with the ZZ genotype. Your specific risks and symptoms should always be discussed with a trained medical professional. See http://alpha-1foundation.org/clinical-resource-centers/ to find an alpha-1 specialist near you.

For those with the ZZ genotype, parents and children are "obligate carriers" of the Z allele. Carriers may wish to know this for lifestyle planning, healthcare management and reproductive decision making. Genetic testing should be considered. Risk for a given individual to be more severely affected depends on which genotypes both of their parents have. It uncommon for multiple generations of a family to be severely affected (SZ, ZZ), though rarely this can occur.

For those with the ZZ genotype, full siblings are at risk to have the ZZ genotype and symptoms of AATD as well. They may also be AATD carriers or unaffected, and not a carrier. Genetic testing is recommended for them to consider.

If you have questions, or have another alpha-1 genotype not discussed above, call the Alpha-1 Foundation genetic counselor in the U.S. at 1-800-785-3177.

References
Who should be tested for alpha-1 antitrypsin deficiency?

According to the 2003 American Thoracic Society (ATS)/European Respiratory Society (ERS) medical guidelines, genetic testing is recommended for: Full siblings of individuals with alpha-1 antitrypsin deficiency (AATD); any adult with chronic obstructive pulmonary disease (COPD), emphysema, or incompletely reversible asthma; adults without symptoms but with persistent obstruction and risk factors; Adults with necrotizing panniculitis; Anyone with unexplained liver disease.

According to the 2003 ATS/ERS Guidelines, genetic testing should be considered for: Parent, child or more distant relative of someone with one or more abnormal SERPINA1 genes; Partner of an affected or carrier with AATD; People with a family history of COPD or liver disease not known to be AATD-related; Adolescents with persistent airflow obstruction; Symptomatic adults in countries with lower AATD incidence.

References
  • American Thoracic Society Documents. American Thoracic Society/European Respiratory Society Statement: Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency. Am J Respir Crit Care Med. Vol 168:818-900. 2003. Retrieved from https://www.alpha1.org/Portals/0/Documents/ATS-ERS-Standards.pdf.
  • Alpha-1 Foundation. Retrieved from https://www.alpha1.org/.
Is screening for alpha-1 antitrypsin deficiency possible during pregnancy?

Genetic carrier screening for alpha-1 antitrypsin deficiency (AATD) is possible during pregnancy. AATD is a condition included on some expanded carrier screens. Expanded carrier screening is an option during pregnancy but it is not standard of care, so many pregnant women do not have carrier screening for AATD or other conditions on these tests. If you are interested in prenatal carrier screening, speak to your healthcare provider about a referral to see a genetic counselor near you. In the U.S., the Alpha-1 Foundation provides free telephone-based genetic counseling and you can reach this service by calling 1-800-785-3177. Genetic counselors can be found on the National Society of Genetic Counselors website.

References
Is there free genetic testing for alpha-1 antitrypsin deficiency?

As of 2017, the Alpha-1 Foundation and Medical University of South Carolina make free and confidential testing available for alpha-1 antitrypsin deficiency. This free testing is part of a research study called the Alpha-1 Coded Testing (ACT) Study. Participants receive a free, at-home test kit after completing an informed consent form and research questionnaire. Results are returned directly to the participant several weeks later. For more information, or to join the ACT Study for a free test kit, visit www.alphaoneregistry.org.

There are also free test kits available to healthcare providers to use in their clinical practice. These kits must be requested from the companies who offer them. Each company that makes an augmentation product for the treatment of alpha-1 antitrypsin deficiency also offers free testing for the condition. More information can be found at www.alpha1.org.

References

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