Alpha-1-antitrypsin deficiency (AATD)

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.

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

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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

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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.