Alpha-1 antitrypsin deficiency (AAT deficiency) is an inherited condition that raises your risk for lung and liver disease. Alpha-1 antitrypsin (AAT) is a protein that protects the lungs. The liver makes it. If the AAT proteins aren't the right shape, they get stuck in the liver cells and can't reach the lungs.

Symptoms of AAT deficiency include

• Shortness of breath and wheezing
• Repeated lung infections
• Tiredness
• Rapid heartbeat upon standing
• Vision problems
• Weight loss

Some people have no symptoms and do not develop complications.

Blood tests and genetic tests can tell if you have it. If your lungs are affected, you may also have lung tests. Treatments include medicines, pulmonary rehab, and extra oxygen, if needed. Severe cases may need a lung transplant. Not smoking can prevent or delay lung symptoms.

Alpha-1 antitrypsin (AAT) deficiency is a genetic condition that raises your risk for lung disease and other diseases.

AAT is a protein. If you do not make enough AAT, your lungs are more easily damaged from cigarette smoking or fumes and dust from the environment. This can lead to serious lung diseases, such as chronic obstructive pulmonary disease, or COPD. AAT deficiency may also cause a liver disease called cirrhosis. This is more common in children who have AAT deficiency. This topic focuses on AAT deficiency that leads to lung disease.

AAT deficiency runs in families. Many people do not know that they have it, but early diagnosis can help prevent serious lung disease. Talk to your doctor if you have a family member who has AAT deficiency or who was diagnosed with COPD in their 40s or 50s. Also, talk to your doctor if you have symptoms such as a chronic (ongoing) cough, shortness of breath, wheezing, or liver disease.

Currently, AAT deficiency has no cure, but a treatment called augmentation therapy may help slow lung damage. You may also need oxygen therapy, pulmonary rehabilitation, or medicines to treat complications. Your doctor may also talk to you about healthy lifestyle changes, such as quitting smoking and avoiding secondhand smoke and other fumes.

Alpha-1 antitrypsin deficiency is an inherited condition that causes low levels of, or no, alpha-1 antitrypsin in the blood.

What is alpha-1 antitrypsin deficiency?

Alpha-1 antitrypsin deficiency (AATD) is an inherited condition that causes low levels of, or no, alpha-1 antitrypsin (AAT) in the blood. AATD occurs in approximately 1 in 2,500 individuals. This condition is found in all ethnic groups; however, it occurs most often in whites of European ancestry.

Alpha-1 antitrypsin (AAT) is a protein that is made in the liver. The liver releases this protein into the bloodstream. AAT protects the lungs so they can work normally. Without enough AAT, the lungs can be damaged, and this damage may make breathing difficult.

Everyone has two copies of the gene for AAT and receives one copy of the gene from each parent. Most people have two normal copies of the alpha-1 antitrypsin gene. Individuals with AATD have one normal copy and one damaged copy, or they have two damaged copies. Most individuals who have one normal gene can produce enough alpha-1 antitripsin to live healthy lives, especially if they do not smoke.

People who have two damaged copies of the gene are not able to produce enough alpha- 1 antitrypsin, which leads them to have more severe symptoms.

What are the symptoms of AATD?

Alpha-1 antitrypsin deficiency (AATD) can present as lung disease in adults and can be associated with liver disease in a small portion of affected children. In affected adults, the first symptoms of AATD are shortness of breath with mild activity, reduced ability to exercise and wheezing. These symptoms usually appear between the ages of 20 and 40. Other signs and symptoms can include repeated respiratory infections, fatigue, rapid heartbeat upon standing, vision problems and unintentional weight loss.

Some Individuals with AATD have advanced lung disease and have emphysema, in which the small air sacs (alveoli) in the lungs are damaged. Symptoms of emphysema include difficulty breathing, a hacking cough and a barrel-shaped chest. Smoking or exposure to tobacco smoke increases the appearance of symptoms and damage to the lungs. Other common diagnoses include COPD (chronic obstructive pulmonary disease), asthma, chronic bronchitis and bronchiectasis - a chronic inflammatory or degenerative condition of one or more bronchi or bronchioles.

Liver disease, called cirrhosis of the liver, is another symptom of AATD. It can be present in some affected children, about 10 percent, and has also been reported in 15 percent of adults with AATD. In its late stages signs and symptoms of liver disease can include a swollen abdomen, coughing up blood, swollen feet or legs, and yellowing of the skin and the whites of the eyes (jaundice).

Rarely, AATD can cause a skin condition known as panniculitis, which is characterized by hardened skin with painful lumps or patches. Panniculitis varies in severity and can occur at any age.

How is AATD diagnosed?

Alpha-1 antitrypsin deficiency (AATD) is diagnosed through testing of a blood sample, when a person is suspected of having AATD. For example, AATD may be suspected when a physical examination reveals a barrel-shaped chest, or, when listening to the chest with a stethoscope, wheezing, crackles or decreased breath sounds are heard.

Testing for AATD, using a blood sample from the individual, is simple, quick and highly accurate.. Three types of tests are usually done on the blood sample:

• Alpha-1 genotyping, which examines a person's genes and determines their genotype.

• Alpha-1 antitrypsin PI type of phenotype test, which determines the type of AAT protein that a person has.

• Alpha-1 antitrypsin level test, which determines the amount of AAT in a person's blood.

Individuals who have symptoms that suggest AATD or who have a family history of AATD should consider being tested.

What is the treatment for AATD?

Treatment of alpha-1 antitrypsin deficiency (AATD) is based on a person's symptoms. There is currently no cure. The major goal of AATD management is preventing or slowing the progression of lung disease.

Treatments include bronchodilators and prompt treatment with antibiotics for upper respiratory tract infections. Lung transplantation may be an option for those who develop end-stage lung disease. Quitting smoking, if a person with AATD smokes, is essential.

Replacement (augmentation) therapy with the missing AAT protein is available, although it is used only under special circumstances. It is not known how effective this is once disease has developed or which people would benefit most.

Is AATD inherited?

Alpha-1 antitrypsin deficiency (AATD) is inherited in families in an autosomal codominant pattern. Codominant inheritance means that two different variants of the gene (alleles) may be expressed, and both versions contribute to the genetic trait.

The M gene is the most common allele of the alpha-1 gene. It produces normal levels of the alpha-1 antitrypsin protein.

The Z gene is the most common variant of the gene. It causes alpha-1 antitrypsin deficiency. The S allele is another, less common variant that causes ATTD.

If a person inherits one M gene and one Z gene or one S gene ('type PiMZ' or 'type PiMS'), that person is a carrier of the disorder. While such a person may not have normal levels of alpha-1 antitrypsin, there should be enough to protect the lungs. However, carriers with the MZ alleles have an increased risk for lung disease, particularly if they smoke.

A person who inherits the Z gene from each parent is called 'type PiZZ.' This person has very low alpha-1 antitrypsin levels, allowing elastase - an enzyme especially of pancreatic juice that digests elastin - to damage the lungs. A person who inherits an altered version called S and Z is also likely to develop AATD.

AAT deficiency can affect people of any race or ethnicity. However, the condition occurs most often in white people of European backgrounds.

If you have first-degree relatives (siblings, parents, or children) with AAT deficiency, you are at a higher risk for the condition. Even so, it does not mean that you will develop one of the diseases related to the condition.

Some risk factors make it more likely that you will develop lung disease if you have AAT deficiency. Cigarette smoking is the leading risk factor for serious lung disease if you have AAT deficiency. Your risk for lung disease also may go up if you breathe in dust, fumes, or other toxic substances.

Alpha-1 antitrypsin (AAT) deficiency happens when you do not make enough AAT protein. The AAT protein is made in your liver. This protein enters your blood and protects your organs, including the lungs, from damage. For example, your immune system is your body’s defense against bacteria and viruses but if it is overactive, it can damage your body while fighting diseases. The AAT protein prevents you from having too much inflammation in your lungs. Without enough AAT protein, your immune system may damage your lungs and lead to lung disease.

AAT deficiency is an inherited disease. “Inherited” means it is passed from parents to children through genes. Every person inherits two AAT genes, one gene from each parent. If you inherit a mutated gene from each parent, you will have AAT deficiency.

If you inherit a mutated AAT gene from one parent and a normal AAT gene from the other parent, you are a carrier for the condition. You might have lower levels of AAT protein in your blood, but you most likely will not have AAT deficiency. However, you might develop some complications of AAT deficiency if you smoke or regularly breathe in dust and fumes. You might also pass the mutated gene to your children.

The AAT gene can have different mutations. The most common mutations that cause AAT deficiency are called PiZ and PiS. The image below shows how mutated AAT genes are passed to children.

Even if you inherit two mutated AAT genes, you may not have any complications. You may never even realize that you have AAT deficiency. Scientists are conducting research to find out why some people who have AAT deficiency develop complications while others do not.

Normal Function

The SERPINA1 gene provides instructions for making a protein called alpha-1 antitrypsin, which is a type of serine protease inhibitor (serpin). Serpins help control several types of chemical reactions by blocking (inhibiting) the activity of certain enzymes. The first identified role for alpha-1 antitrypsin was to control the activity of the digestive enzyme trypsin. Alpha-1 antitrypsin also inhibits other enzymes, including a powerful enzyme called neutrophil elastase that is released from white blood cells to fight infection.

Alpha-1 antitrypsin is produced in the liver and then transported throughout the body via the blood. Alpha-1 antitrypsin protects the lungs from neutrophil elastase, which can damage lung tissue if not properly controlled.

Health Conditions Related to Genetic Changes

Alpha-1 antitrypsin deficiency

More than 100 variants (also known as mutations) in the SERPINA1 gene have been associated with a condition called alpha-1 antitrypsin deficiency. This condition is characterized by a shortage (deficiency) of the alpha-1 antitrypsin protein, which increases a person's risk of developing lung disease, liver disease, and other abnormalities.

Many SERPINA1 gene variants change single protein building blocks (amino acids) in alpha-1 antitrypsin, which can alter the protein's structure. The most common variant that causes alpha-1 antitrypsin deficiency replaces the amino acid glutamic acid with the amino acid lysine at protein position 342 (written as Glu342Lys or E342K). This genetic change creates a version of the SERPINA1 gene called the Z allele. Another common variant creates a version of the gene called the S allele. This variant replaces the amino acid glutamic acid with the amino acid valine at protein position 264 (written as Glu264Val or E264V). (The unaltered version of the SERPINA1 gene is known as the M allele.)

Abnormal alpha-1 antitrypsin proteins, including those produced from the Z allele, may bind together to form a large molecule, or polymer, that cannot leave the liver. The accumulation of these polymers results in liver damage. In addition, lung tissue is destroyed because there is not enough alpha-1 antitrypsin available to protect against neutrophil elastase. Polymers of alpha-1 antitrypsin may also contribute to excessive inflammation, which may explain some of the other features of alpha-1 antitrypsin deficiency, such as a skin condition called panniculitis.

The S allele and some other SERPINA1 gene variants lead to the production of an abnormal form of alpha-1 antitrypsin that is quickly broken down in the liver. Still other gene variants prevent the production of any alpha-1 antitrypsin protein. As a result, little or no alpha-1 antitrypsin is available in the lungs. While the liver remains healthy in individuals with these variants, the lungs are left unprotected from neutrophil elastase.

Other Names for This Gene

• A1A
• A1AT
• A1AT_HUMAN
• AAT
• alpha-1 antiproteinase
• alpha-1 antitrypsin
• alpha-1 proteinase inhibitor
• alpha1AT
• PI
• PI1
• protease inhibitor 1 (anti-elastase)
• serine protease inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1
• serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1

Genomic Location

This condition is inherited in an autosomal codominant pattern. Codominance means that two different versions of the gene may be active (expressed), and both versions contribute to the genetic trait.

The most common version (allele) of the SERPINA1 gene, called M, produces normal levels of alpha-1 antitrypsin. Most people in the general population have two copies of the M allele (MM) in each cell. Other versions of the SERPINA1 gene lead to reduced levels of alpha-1 antitrypsin. For example, the S allele produces moderately low levels of this protein, and the Z allele produces very little alpha-1 antitrypsin. Individuals with two copies of the Z allele (ZZ) in each cell have a high risk of developing lung disease (such as emphysema) and liver disease associated with alpha-1 antitrypsin deficiency. Those with the SZ combination have an increased risk of developing lung disease, particularly if they smoke.

Worldwide, it is estimated that 185 million people have one copy of the S or Z allele and one copy of the M allele in each cell (MS or MZ). Individuals with an MS (or SS) combination usually produce enough alpha-1 antitrypsin to protect the lungs. People with MZ alleles, however, have a slightly increased risk of impaired lung or liver function.

The first lung-related symptoms of AAT deficiency may include shortness of breath, less ability to be physically active, and wheezing. Some people may not have any symptoms or complications. AAT deficiency can lead to lung and liver diseases.

Signs and symptoms

Symptoms of AAT deficiency include:

• Chronic (ongoing) cough
• Feeling tired (fatigue)
• Repeat lung infections
• Shortness of breath or problems breathing
• Wheezing

These symptoms usually appear in people between 20 and 50 years old. At first, many people who have AAT deficiency are diagnosed with asthma. This is because wheezing also is a symptom of asthma. Also, people who have AAT deficiency respond well to asthma medicines.

Some people who have AAT deficiency may have liver damage. Signs of liver damage include jaundice and swelling in your legs. Rarely, AAT deficiency can cause skin problems, such as painful lumps or patches.

Complications

AAT deficiency can lead to:

• Asthma
• Bronchiectasis
• Cirrhosis, a type of liver disease
• COPD. Some people who have severe AAT deficiency develop emphysema, a condition that is part of COPD, often when they are only in their 40s or 50s.
• Respiratory failure
• Vasculitis, which is inflammation in the blood vessels

Early diagnosis can help you prevent serious complications by avoiding risk factors such as smoking.

AAT deficiency usually is diagnosed after you develop a lung or liver disease that is related to the condition. But knowing the symptoms and getting an early diagnosis is important to help prevent serious disease, especially with treatment and lifestyle changes.

You may see different specialists, or your doctor may order several diagnostic tests to diagnose AAT deficiency.

Medical history and physical exam

Your doctor will ask about your risk factors. This includes your lifestyle habits and environment, such as smoking or regularly breathing in dust. Your doctor will ask if you have relatives who have AAT deficiency or a lung or liver disease and whether you have any signs or symptoms of lung disease. Your doctor will also do a physical exam including listening to your lungs.

Diagnostic tests

Your doctor may recommend tests to confirm a diagnosis of AAT deficiency. He or she also may recommend tests to check for lung- or liver-related conditions.

• A blood test can check the level of AAT protein in your blood. If the level is lower than normal, it is likely that you have AAT deficiency.
• Agenetic test is the most certain way to check for AAT deficiency and should be done to confirm the results of the blood test and find the mutation in the AAT gene. A genetic counselor can help you understand what to expect from a genetic test and what your results mean.

Lung tests

If you have a lung disease related to AAT deficiency, your doctor may recommend pulmonary (lung) function tests and imaging tests such as a chest CT scan.

Lung function tests measure how much air you can breathe in and out, how fast you can breathe air out, and how well your lungs deliver oxygen to your blood. CT scans use X-rays to create detailed pictures of parts of the body.

These tests show how well your lungs are working and whether you have COPD or other lung diseases.

AAT deficiency currently has no cure, but there are treatments to slow lung damage and treat its complications. Treatment is best managed by a team that includes a primary care doctor, pulmonologist (lung specialist), gastroenterologist (GI specialist), and geneticist (specialist in genetic conditions). People who have AAT deficiency and develop related liver or skin diseases will be referred to doctors who treat those diseases.

You may need a lifelong treatment called augmentation therapy. In this treatment, you receive the AAT protein, obtained from blood donors, through a vein to raise levels of the protein in your lungs. This helps slow down lung damage. Side effects of this treatment are rare and may include a mild fever, headaches, nausea, and dizziness.

If you have complications from AAT deficiency, you may also need:

• Medicines called inhaled bronchodilators and inhaled steroids. These medicines help open your airways and make breathing easier. They are also used to treat asthma and COPD.
• Oxygen therapy
• Pulmonary rehabilitation, which involves treatment by a team of experts at a special clinic. You will learn how to manage your condition and function at your best.
• A lung transplant, which may be an option if you have very severe breathing problems and have a good chance of surviving the transplant surgery

You may want to talk to your doctor about testing for AAT deficiency if you have a parent, sibling, or child with the condition, even if you do not have symptoms.

There is no way to prevent AAT deficiency because the condition is inherited. You may want to talk to a genetic counselor if you are planning to have children and think they are at risk of having AAT deficiency. A genetic counselor can answer questions about the risk and explain the choices that are available.

If you have AAT deficiency, you can take steps to prevent or delay lung diseases related to AAT deficiency. One important step is to quit smoking. If you do not smoke, do not start.

Talk with your doctor about programs and products that can help you quit smoking. If you have trouble quitting smoking on your own, consider joining a support group. Many hospitals, workplaces, and community groups offer classes to help people quit smoking.

Also, try to avoid secondhand smoke and places with dust, fumes, or other toxic substances that you may inhale. Check your living and working spaces for things that may irritate your lungs. Examples include flower and tree pollen, ash, allergens, air pollution, wood-burning stoves, paint fumes, and fumes from cleaning products and other household items.

If you already know you have AAT deficiency, you probably also have a related lung or liver disease. Ongoing medical care and lifestyle changes can help you manage your health. Your doctor may also talk to you about making healthy lifestyle changes such as quitting smoking, avoiding secondhand smoke and other lung irritants, and getting annual flu and pneumonia vaccines.

Manage your condition

Regular follow-up care is important to help you manage your health.

• Talk with your doctor about how often you should schedule medical visits. You may need regular pulmonary (lung) function tests or imaging tests to monitor your condition.
• Get flu and pneumococcal vaccines to protect you from illnesses that may worsen your condition.
• Take all your medicines as prescribed and follow your treatment plan.
• If you have a lung infection, get treatment right away. You also should get treatment right away for any breathing problems.

If you have COPD, your doctor may recommend regular monitoring for heart disease, asthma, depression, and diabetes. COPD can increase your risk for these conditions or make them worse.

Make healthy lifestyle changes

Your doctor may talk to you about making healthy lifestyle changes, which can help you function at your best.

• Quit smoking. If you smoke, quit. If you do not smoke, do not start. Smoking is the leading risk factor for life-threatening lung disease if you have AAT deficiency.
• Avoid secondhand smoke and other lung irritants, such as dust, fumes, or toxins. Check your living and working spaces for things that may irritate your lungs. Examples include flower and tree pollen, ash, allergens, air pollution, wood burning stoves, paint fumes, and fumes from cleaning products and other household items.
• Choose healthy foods. Choose vegetables, fruits, whole grains, fat-free or low-fat dairy products, fish, lean meats, poultry, eggs, nuts, seeds, soy products, legumes, and vegetable oils (except coconut and palm oils). Also, limit sodium (salt), saturated and trans fats, added sugars, and alcohol. Talk with your doctor about whether it's safe for you to drink alcohol.
• Get regular physical activity. Talk with your doctor about how much and what types of activity are safe for you.
• Manage stress. Learning how to manage stress, relax, and cope with problems can improve your emotional and physical health. Relaxation techniques—such as meditation, yoga, breathing exercises, and muscle relaxation—can help you cope with stress.
• Get enough good quality sleep. The recommended amount for adults is 7 to 9 hours of sleep a day.

Take care of your mental health

Living with AAT deficiency may cause fear, anxiety, depression, and stress. Talk about how you feel with your healthcare team. Talking to a professional counselor also can help. Your doctor may also talk to you about:

• Taking medicines or undergoing other treatments that can improve your quality of life
• Joining a patient support group, which may help you adjust to living with AAT deficiency. You can see how other people have managed their condition, as well as similar symptoms. Talk with your doctor about local support groups or check with an area medical center.
• Seeking support from family and friends, which may help relieve stress and anxiety. Let your loved ones know how you feel and what they can do to help you.