Alpha-1-antitrypsin deficiency

Overview

Alpha-1-antitrypsin deficiency (AATD) is a condition that's passed through families, called inherited. It can cause damage to the lungs, liver, skin and blood vessels. Not everyone who has AATD develops symptoms or health concerns. People in the same family may have different symptoms.

Genes control how every cell in the body works. Some genes decide basic traits, such as eye color or hair color. Other genes can increase the risk of getting certain diseases, including AATD.

One gene tells the liver to make alpha-1-antitrypsin (AAT or A1AT) protein. This protein travels through the bloodstream to protect the lungs from smoke, pollution, fumes or dust that is breathed in.

But in people who have AATD, gene changes cause the liver to either not make enough AAT protein or make protein that isn't formed correctly. These gene changes also are called variants. Researchers have found more than 120 variants that are linked to AATD.

In the lungs, a lack of AAT protein can lead to emphysema or ongoing bronchitis. These are forms of chronic obstructive pulmonary disease (COPD). The lack of protein also can lead to bronchiectasis. In the liver, AATD that builds up can cause fibrosis and cirrhosis. AATD also can increase the risk of liver cancer.

AATD has no cure. But with early diagnosis and the right care, many people with AATD can prevent serious problems or control symptoms and improve their quality of life. Some people who have never smoked may live a typical lifespan. However, they may still develop lung disease, liver disease or both.

Symptoms

AATD symptoms depend on which organs are affected and how severe the condition is. Symptoms can vary within families.

Symptoms typically start in adults older than 30 years old. But children also may have symptoms of liver disease. Not everyone who has AATD has symptoms.

AATD most often affects the lungs and liver. But AATD can affect skin and blood vessels.

Lungs

The AAT protein that usually protects the lungs doesn't work well or there isn't enough. Lungs can be more easily damaged from smoke, air pollution, fumes and dust. Cigarette smoke is the most common cause of lung disease.

Symptoms of lung disease may include:

• Trouble catching your breath.
• Wheezing when you breathe.
• Lack of energy or feeling very tired.
• Limited ability to exercise or do your regular activities.
• Ongoing cough that may bring up a lot of mucus.
• Frequent lung infections.

Lung disease caused by AATD is rare in children.

Liver

The liver makes the AAT protein. But if the AAT protein isn't formed correctly, the protein builds up in the liver, potentially causing scarring that can progress to end-stage liver disease or cirrhosis. Symptoms of liver disease may include:

• Yellowing of the skin and the white part of the eyes, called jaundice. Yellowing of the skin might be harder to see on Black or brown skin.
• Losing weight without trying to.
• Not feeling hungry or not wanting to eat.
• Swelling in the legs or belly.
• Lack of energy or feeling very tired.
• Throwing up blood or blood in stools.

Symptoms of liver disease may be different in children. Infants may have jaundice that doesn't go away, swelling in the belly, dark urine or pale stools.

Skin

AATD can damage the skin, but this is rare. Symptoms may include:

• Painful lumps in the fat below the skin. Lumps most often affect the lower belly and legs.
• Painful sores on the skin.
• Hot patches on the skin over the lumps. Patches may affect the legs, lower belly, thighs and buttocks.

Rarely, skin diseases can affect newborns and children.

Blood vessels

AATD can cause inflammation of the blood vessels. This is rare. Symptoms may include:

• Aches and pains all over.
• Feeling tired.
• Fever.
• Not feeling hungry or not wanting to eat.
• Losing weight without trying.

Symptoms of blood vessel swelling are rare in children.

When to see a doctor

If you or your child has symptoms of lung, liver, skin or blood vessel disease, talk with your healthcare professional about testing for the condition. Talk with your healthcare professional if someone in your family has AATD, lung disease or liver disease.

Causes

AATD is caused by a change in the SERPINA1 gene. This is the gene that tells the body to make the AAT protein.

The AAT protein is known as a protease inhibitor (PI). An inhibitor stops something from happening or keeps it in check. The AAT protein helps control protease enzymes produced in the body. These enzymes, such as the neutrophil elastase enzyme, can destroy lung tissue. So keeping protease enzymes in check helps protect lung tissue.

AATD is an autosomal dominant condition. Each person inherits two copies of the SERPINA1 gene, one from the mother and one from the father. Having two variants of the gene means you have AATD.

Having one variant of the gene means you are a carrier for AATD. You likely won't develop AATD complications. But you could pass the changed gene to your children.

Gene changes

Different types of gene changes affect how much AAT protein is made and how well it works. AATD can affect people in different ways. People may have AATD and not even know it.

If the liver doesn't make enough AAT protein or if the AAT protein doesn't work as it should, the neutrophil elastase enzyme attacks lung tissue, causing it to break down. This increases the risk of lung diseases such as COPD.

AAT protein that builds up in the liver may cause liver damage. This increases the risk of liver diseases such as cirrhosis.

Testing the SERPINA1 gene can tell which variant potentially puts a person at an increased risk of lung, liver, skin and blood vessel conditions. Variants are grouped into categories of how the variants affect the AAT protein's quantity or quality.

Variants are assigned a letter based on how the protein moves when it's stimulated by an electric charge. For example, AAT protein that looks and works as it should has the letter M. And AAT protein with low quantity or quality has either the letter S or Z. Having an S or Z variant raises the risk of AATD.

Together, two variants — one from each parent — determine the increased risk of lung or liver diseases. This pair of variants is known as a genotype. The MM genotype has the lowest risk of AATD. The ZZ genotype has the highest risk of AATD.

Different combinations of genetic changes can increase the risk of certain conditions. The genotypes are written with an asterisk.

• PI*MM, PI*MS and PI*SS can cause:
  • Emphysema, which is a lung condition. The risk appears to be the same as in people who don't have AATD. There isn't an increased risk.
• PI*MZ can cause:
  • COPD in people who smoke or have long-term exposure to pollutants and fumes. People who don't smoke typically aren't at increased risk of emphysema.
  • Liver disease. The risk of liver cirrhosis is slightly increased.
• PI*SZ can cause:
  • Emphysema and bronchitis. The risk is higher in people who smoke.
  • Liver cirrhosis. This risk is nearly tripled.
  • Hepatocellular cancer, the most common type of liver cancer. This risk is higher than in a person who doesn't have AATD.
• PI*ZZ can cause:
  • Nearly all of the severe AATD cases.
  • Liver fibrosis and cirrhosis. The risk is high.
  • Hepatocellular cancer.
  • Emphysema and COPD. The risk is very high, especially among people who smoke.
  • Panniculitis and vasculitis.
• PI*null-null — no AAT protein — can cause:
  • Lung disease. The risk is nearly 100%. The liver is not at risk because it doesn't make the AAT protein.

Risk factors

Risk factors for AATD include:

• Family history of AATD. AATD is a condition passed down in families. AATD affects about 100,000 people living in the United States and more than 3 million people globally. AATD is most common in people of Northern European ancestry, but it occurs in people of all ancestries. Gene variants have been reported in different parts of Europe, Africa, Asia and South America. AATD is underdiagnosed across the world, especially among people who are Black, Asian or of Latin American descent.
• Family history of COPD or emphysema. For about 1% of people diagnosed with COPD, it is inherited. The biggest risk factor for COPD is long-term cigarette smoking. The more years you smoke and the more packs you smoke, the greater the risk.
• Family history of liver disease.

Complications

Complications of AATD can affect the lungs, liver, skin or blood vessels.

Lungs

People who have AATD can damage their lungs by repeated exposure to smoke, fumes, air pollution or dust. People with AATD who smoke typically develop lung disease between ages 40 and 50 — about 10 years sooner than people who don't smoke. Lung disease can start in someone who has AATD in their 30s. Smoking increases the risk of lung disease, and smoking causes more-severe lung disease than in someone who doesn't smoke.

Causes of airway obstruction

AATD raises the risk of a group of lung diseases known as chronic obstructive lung disease (COPD). COPD is an ongoing lung condition caused by damage to the lungs. Swelling and irritation can block airflow and create extra mucus, which makes breathing hard.

The two most common types of COPD are:

• Emphysema. Emphysema damages the walls of the air sacs in the lungs called alveoli. In healthy lungs, the sacs stretch and fill with air when you breathe in. The sacs help air leave the lungs when you breathe out. But damage from emphysema causes the walls to break down. Air gets trapped in the large alveoli. This makes it hard for new oxygen-rich air to get in.

  Cigarette smoking speeds up the development of the disease and lung damage. About 9 in 10 people who have severe AATD and smoke develop emphysema. But people with AATD who don't smoke also can get emphysema.

• Chronic bronchitis. Bronchitis is the inflammation of the tubes that carry oxygen to and from the lungs. The tubes are called bronchial tubes. The ongoing swelling causes extra mucus. People who smoke may have symptoms as early as age 35. About 4 in 10 people who have AATD have ongoing bronchitis.

In people who have AATD, COPD usually develops before age 55. Lung disease is most common in people older than 30. Lung diseases are more common in adults than in children.

Liver

SERPINA1 gene changes can change the shape of the AAT protein. When the liver can't move the AAT protein into the bloodstream, the protein builds up and has nowhere to go. Over time, this buildup can cause damage. Liver disease can start at any age, including at birth.

AATD raises the risk of liver diseases:

• Fibrosis. Scar tissue builds on the liver over areas of swelling or injury. Men older than 50 who have AATD, diabetes and obesity are at high risk of fibrosis. Scarring that gets worse over time can lead to cirrhosis.
• Cirrhosis. Scar tissue that builds on the liver affects how well the liver works. Advanced scarring of the liver is called cirrhosis. It can lead to liver failure and liver cancer. Cirrhosis is known as end-stage liver disease.
• Liver cancer. AATD increases the risk of liver cancer. Hepatocellular cancer is the most common liver cancer in people with AATD. It occurs most often in people who have cirrhosis.

Infants can get liver disease. AATD is the main cause of liver disease in children. Adults can get liver disease if they didn't have it during childhood.

Skin

People with AATD have an increased risk of a skin condition called panniculitis. Swelling of tissue under the skin can cause painful lumps. Lumps often appear in the lower belly and legs.

Painful patches or lumps also can appear on the skin. They most often form on the thighs and buttocks. The lumps may break open and leak an oily liquid.

The average age panniculitis occurs is about age 40. Panniculitis is rare.

Blood vessels

AATD raises the risk of a group of blood vessel conditions called vasculitis. Blood vessels become damaged because of swelling called inflammation. Either arteries or veins can be affected. Swelling on the walls of blood vessels narrows or blocks blood flow. Vasculitis also can cause blood clots, which could cause a heart attack or stroke.

Some blood vessel damage can cause death. Vasculitis is rare.

Prevention

AATD can't be prevented. But you may be able to prevent or slow COPD. The best way to prevent COPD is to never smoke. If you smoke, quit. Stopping now can slow how fast the condition gets worse.

If you have a family history of AATD or you're in an ethnic group that has a high risk of a specific genetic disorder, you may choose to have genetic testing before having children. Single gene testing can identify if you or your partner has gene variants that could be passed to your children.

Diagnosis

AATD is a rare disease that can be difficult to diagnose. Diagnosis often occurs late, often more than five years after lung disease symptoms start. A blood test can measure the AAT protein level in your blood. Your healthcare professional may recommend a blood test if you have:

• Symptoms of AATD.
• A lung disease such as COPD, especially if it started before age 55.
• A liver disease such as cirrhosis.
• Close family members, such as a parent or sibling, who have AATD.
• Close family members who have lung or liver disease.

Tests

Your healthcare professional might suggest other tests to check for possible complications of the disease if you or your child has a low level of AAT protein. Tests could include:

• Genetic test. A genetic test is a blood test that can find the exact changes in the SERPINA1 gene. A genetic counselor can explain your test results and what the gene variants mean. Genetic testing isn't for everyone. Before you decide to be tested, talk with a genetic counselor about the mental health impact the test results might have.
• Lung function tests. Lung function tests, such as spirometry, can tell how well your lungs are working. If you have COPD, you may have regular spirometry testing. Lung function tests also are called pulmonary tests.
• Imaging tests. Imaging tests, such as a CT scan of your lungs or an X-ray of your chest, can show lung damage from COPD. Your healthcare professional may want you to have a CT scan of your chest if you have emphysema. You also may have a CT scan if you are newly diagnosed with AATD and have lung disease symptoms.
• Liver tests. Blood tests and imaging tests, such as ultrasound, can tell how well your liver is working.

Treatment

There is no cure for AATD, but treatment can help you live a healthier life. You can manage your symptoms and lower your risk of complications. This can help you live a healthier life.

AATD treatment depends on the lung, liver, skin or blood vessel complication. AATD treatment doesn't depend on your genetic makeup.

Work with your healthcare professional to create a personalized plan.

Lung diseases

Your treatment plan is based on your symptoms and how severe they are.

AATD-specific treatment replaces missing AAT protein through infusions. Standard COPD therapy includes medicines, oxygen therapy and pulmonary rehabilitation. Surgery or a lung transplant may help if COPD symptoms no longer respond to treatment.

Treatment can help you manage symptoms, slow how fast the condition worsens, lower the risk of complications and improve your ability to lead an active life. Treatment options may include the following.

• IV infusions of the AAT protein. Some people can raise their AAT protein levels through weekly infusions of AAT from donors. Known as augmentation therapy, infusions of AAT into a vein may slow damage to the lungs caused by emphysema. This therapy is typically for people who have the lowest AAT levels. It has some side effects.
• Medicines. Medicines help you breathe better. Most medicines are given with an inhaler. This small hand-held device delivers the medicine straight to your lungs when you breathe in the fine mist or powder. Some medicines are used when needed, and others are used every day. The most common medicines used to treat COPD include:
  • Bronchodilators. These relax the muscles around the airways and can help clear mucus. Depending on how severe your COPD is, you may need a short-acting bronchodilator before activities, a long-acting bronchodilator that you use every day or both.
  • Inhaled corticosteroids. Also called steroids, these help reduce airway swelling. Inhaled steroids help prevent bouts when COPD symptoms get worse.
  • Antibiotics. These help treat a flare-up of symptoms caused by a respiratory infection such as influenza or pneumonia. Flare-ups also are called exacerbations.
• Oxygen therapy. Oxygen therapy can improve quality of life and extend life. If there isn't enough oxygen in your blood, supplemental oxygen can help. Oxygen enters your body through a tube that rests in your nostrils or from a face mask. These attach to an oxygen tank. Some people with COPD use oxygen only during activities or while sleeping. Others use oxygen all the time.
• Pulmonary rehabilitation. This program combines exercise training, breathing techniques and health education. All sessions are supervised by healthcare professionals. You work with a variety of specialists. Pulmonary rehabilitation allows you to participate more fully in everyday activities and improves your quality of life.
• Surgery. Surgery may be an option for some people if medicines don't effectively treat serious symptoms. Surgical options include:
  • Bullectomy. Large air spaces called bullae form in the lungs when the inner walls of the air sacs are destroyed. This leaves one large air sac instead of a group of many smaller ones. These bullae can become very large and cause breathing problems. In a bullectomy, the surgeon removes one or more bullae from the lungs.
  • Lung volume reduction surgery. In lung volume reduction surgery, the surgeon removes wedges of damaged lung tissue from the upper lungs. This creates extra space in the chest so the healthier lung tissue that remains can expand. The muscle that helps in breathing, called the diaphragm, can work better. In some people who have severe emphysema, this surgery can improve quality of life and help them live longer. Surgery also increases their ability to exercise.
  • Lung transplant. A lung transplant may be an option for some people who have severe or end-stage lung disease. Replacing a lung can make breathing easier and help you live longer. But it's major surgery that has significant risks, such as organ rejection. A lung transplant requires taking lifelong medicine that weakens the immune system.

Liver diseases

Standard treatment for liver disease depends on the cause and extent of liver damage. Treatment includes monitoring and medicines. A liver transplant may be considered for end-stage liver disease. The goals of treatment are to slow the progression of scar tissue in the liver and to prevent or treat symptoms and complications of cirrhosis. Treatment options may include:

• Monitoring. Your healthcare professional may schedule yearly tests to see how well your liver is working. Tests may include liver function tests, ultrasound and MRI. You may need tests more often if you have liver cancer and cirrhosis or if you have liver function tests that keep showing results outside the reference range.
• Liver transplant. Liver transplant may be an option for some people who have end-stage liver disease. Replacing a liver can help you live longer. But it's major surgery that has significant risks, such as organ rejection. A liver transplant requires taking lifelong medicine that weakens the immune system.
• Experimental medicine. Researchers are working on therapies that will specifically target liver cells, helping to slow or even reverse the fibrosis that leads to cirrhosis. Fazirsiran is an experimental medicine that targets the changed gene. It has shown early promise by reducing the amount of misshapen AAT protein that collects in the liver. More clinical trials are needed to confirm how well fazirsiran works to reduce fibrosis.

IV infusions of the AAT protein don't help improve liver disease. For this reason, infusions of the AAT protein aren't recommended.

Skin disease

Your treatment plan for panniculitis is based on your symptoms and how severe they are. If left untreated, panniculitis can lead to death. Treatment options may include:

• Medicines. Dapsone is a tablet taken for several weeks to treat skin infections. Dapsone has known side effects. Dapsone is often the first medicine prescribed for panniculitis. Doxycycline is a tetracycline antibiotic that may be prescribed with dapsone.
• IV infusions of the AAT protein. Boosting AAT levels through weekly infusions of donated AAT into a vein may help some people when dapsone isn't effective. Dosing levels are typically higher than given to treat people with emphysema. There are some side effects. AAT protein infusions are considered off-label to treat panniculitis. Although some healthcare professionals believe infusions are helpful, insurance providers may not pay for treatment.

Blood vessel

Your treatment plan for vasculitis is based on your symptoms and how severe they are. Treatment options may include medicine or surgery.

• A corticosteroid medicine is the most common type of medicine prescribed to control the inflammation of vasculitis. Corticosteroids can have bad side effects. The longer you take them, the worse the side effects may be. Your healthcare professional may add other medicines to corticosteroids to control the inflammation. That way, you can lower the dose of corticosteroids more quickly.
• Sometimes, vasculitis causes a balloonlike bulge in the wall of a blood vessel. This is called an aneurysm. This bulge may need treatment with surgery to lower the risk of it breaking.

Lifestyle and home remedies

Your healthcare team works with you to identify the lifestyle changes that help you most. The following ways might help you avoid complications or slow damage to your lungs and liver:

• Quit smoking. Stopping smoking can keep COPD from getting worse and help you breathe easier. For people with severe AATD, smoking may shorten how long they live — by as much as 10 years. Talk with your healthcare professional about stop-smoking programs, nicotine replacement products and medicines that might help.
• Avoid smoke and poor-quality air. Avoid places where other people smoke. Secondhand smoke may add to lung damage. Dust, fumes and air pollution also may hurt your lungs and cause COPD flare-ups. Check daily air quality forecasts before you go outdoors. Stay indoors when there's a lot of pollution, smoke or dust in the air.
• Avoid alcohol. Talk with your healthcare professional about whether you need to stop using alcohol. Do not drink alcohol if you have a liver disease. Alcohol can make liver disease worse. When comparing people with liver transplants, those who don't drink alcohol live longer than those who do drink alcohol.
• Eat healthy foods. Eating nutrient-rich foods helps you feel better and increases your strength. These foods also can help you maintain a healthy weight. Nutrient-rich foods include vegetables, fruits, nuts, lean proteins, whole grains and dairy. A healthcare professional may recommend nutritional supplements, especially if you are underweight.
• Get regular physical activity. Regular daily activities and exercise can strengthen the muscles you use to breathe. Exercise that blends movement with breathing, such as tai chi or yoga, may help your lungs work better. This makes it easier to stay active. Regular activity also increases your appetite and improves your mood. Exercise also may help you maintain a healthy weight. Talk with your healthcare professional about which exercises are best for you.
• Stay up to date with vaccines. Vaccines help protect your lungs and liver from serious infections. Get regular COVID-19, flu and pneumonia shots, and hepatitis A and hepatitis B vaccines. Ask your healthcare professional if you need other vaccines, such as respiratory syncytial virus, tetanus, measles and shingles.
• Review your medicines. Ask a healthcare professional or pharmacist to review the medicines you take. Check if you take any medicines that may cause liver damage. Include all medicines you can buy with a prescription and without a prescription.

Coping and support

Living with AATD can be a challenge. If you or your child has AATD, you may have strong emotions such as depression, anxiety or fear. These tips may help.

• Get professional help. If you or your child is depressed or anxious, it may help to meet with a mental health professional. You can talk about feelings and ways to cope. The mental health professional may suggest medicines or other treatments too.
• Find support. Talking openly about how you feel can help. It also may help to talk with others who have the same condition. That might mean joining a support group.
• Spend time with friends and family. Having their support can help you manage stress and lessen anxiety. Ask your friends or family for help when you need it.

Preparing for an appointment

Here's some information to help you get ready for your appointment.

What you can do

When you make the appointment, ask if there's anything you need to do before you arrive, such as fasting before having a certain test.

Before your appointment, make a list of:

• Symptoms you're experiencing and when they started. Include anything that makes your symptoms worse or better.
• All medicines, vitamins, herbs and supplements you take. Include the doses.
• Family history, such as whether anyone in your family has a lung or liver disease.
• Treatment you've had for any lung or liver disease, if any. Include what the treatment was and if it helped.
• Any other medical conditions you have and their treatments.
• Your smoking history, including if you smoke or have ever smoked.
• Questions to ask your healthcare professional.

Take a family member or friend along, if possible, to help you remember what your healthcare team tells you.

Questions to ask may include:

• What's likely causing my symptoms?
• What tests do I need?
• Is my condition likely to go away or last?
• What treatment do you suggest?
• I have these other health conditions. How can I best manage them together?
• Are there restrictions I need to follow?
• Should I see a specialist?
• Are there brochures or other printed material I can have? What websites do you suggest?

Be sure to ask all the questions you have.

What to expect from your doctor

Your healthcare professional is likely to ask you questions, such as:

• Have your symptoms been ongoing or do they come and go?
• How bad are your symptoms?
• What, if anything, seems to make your symptoms better?
• What, if anything, seems to make your symptoms worse?
• Do you now or have you ever smoked cigarettes? If you smoke, would you like help in quitting?
• Do you find it hard to catch your breath, even with little or no activity?
• Do you have a family history of lung or liver disease?
• Have you ever had jaundice?
• How often do you drink alcohol?

Be ready to answer questions so that you have time to talk about what's most important to you.