Alpha-1 Antitrypsin Deficiency (Alpha-1) is a genetic (inherited) condition – it is passed from parents to their children through their genes. Alpha-1 may result in serious lung disease in adults and/or liver disease at any age.
For each trait a person inherits, there are usually two genes; one gene comes from each parent. People with Alpha-1 have received two abnormal alpha-1 antitrypsin genes. One of these abnormal genes came from their mother and one from their father.
The abnormal Alpha-1 genes
There are many types of abnormal alpha-1 antitrypsin genes. The most common abnormal genes are called S and Z. Normal genes are called M. A person who does not have Alpha-1 will have two M genes (MM).
People identified with Alpha-1 most commonly have two Z genes (ZZ). Current evidence suggests that there are about 100,000 people with Alpha-1 (ZZ) in the United States.
Another deficient gene combination is SZ, although people with this gene combination are less likely to get lung or liver problems than those with two Z genes.
Alpha-1 occurs when there is a lack of a protein in the blood called alpha-1 antitrypsin, or AAT. AAT, the alpha-1 protein, is mainly produced by the liver.
The main function of AAT is to protect the lungs from inflammation caused by infection and inhaled irritants such as tobacco smoke.
The low level of AAT in the blood occurs because the AAT is abnormal and cannot be released from the liver at the normal rate.
This leads to a build-up of abnormal AAT in the liver that can cause liver disease and a decrease of AAT in the blood that can lead to lung disease.
How is alpha-1 antitrypsin deficiency inherited?
In order to develop A1AT deficiency, a person has to have two copies of the faulty gene on chromosome 14 – they have to have inherited a copy of the faulty gene from both of their parents.
If they just inherit a copy of the faulty gene from one of their parents, they do not develop A1AT deficiency.
They can still make enough normal A1AT to protect their lungs from damage. But, they are a carrier of A1AT deficiency – they can pass on the faulty gene to any children that they have.
There are many variations of the A1AT faulty gene. People with certain gene variations can be more severely affected than others. It has all got to do with the amount of normal A1AT that they are still able to produce.
Only people with the lowest levels of A1AT in their blood will develop symptoms. A special test known as a phenotype test can show the gene variation that a person has.
People who have two copies of the Z-type faulty gene (people who have the ZZ phenotype) produce the least amount of normal A1AT and are most severely affected.
How common is alpha-1 antitrypsin deficiency?
Between 1 in every 3,000 to 5,000 people in the UK have A1AT deficiency. Around 1 in 25 people carry an A1AT faulty gene. This makes A1AT deficiency one of the most common inherited conditions in the UK.
What are the symptoms of alpha-1 antitrypsin deficiency?
Because of the variations of the A1AT faulty gene mentioned above, there is a wide range of symptoms that people with A1AT deficiency may have. Some people with A1AT deficiency have very few or no symptoms, whilst others are more severely affected.
Also, the variations in the faulty gene mean that symptoms can progress more quickly in some people than in others. Someone with A1AT deficiency can develop lung symptoms or liver symptoms, or sometimes both.
These are the most common. If lung symptoms develop, it is not usually until a person is in their 40s. However, people who smoke and who also have A1AT deficiency tend to develop symptoms much earlier, sometimes as early as in their 20s. Symptoms can include:
- Shortness of breath – at first, this may just be feeling short of breath on exertion but the shortness of breath can gradually get worse (over several years) and some people can eventually develop severe breathing difficulties.
- Cough – this is another common symptom. Some people with A1AT deficiency can bring up a lot of sputum when they cough.
- Chest infections – people with emphysema tend to develop more frequent chest infections. Their other symptoms (shortness of breath, cough, wheeze) tend to get worse, or flare up, during a chest infection.
- Liver symptoms
Rarely, a baby with A1AT deficiency can develop jaundice and liver inflammation (hepatitis) soon after they are born.
It is thought to be due to a build-up of A1AT in the baby’s liver while they were developing in their mother’s womb.
Most of the time, the child will grow out of their liver problems so that, by the time they reach puberty, they may only have mild liver abnormalities. However, in some rare cases, a baby or young child can develop liver failure.
Many adults with A1AT deficiency will show some signs of mild liver damage. But, in a few, more severe liver damage can occur, leading to scarring (known as liver cirrhosis) and chronic liver disease where their liver isn’t working very well.
How is alpha-1 antitrypsin deficiency diagnosed?
A simple blood test can diagnose A1AT deficiency. Levels of A1AT in the blood will be low in people with A1AT deficiency.
A phenotype blood test is usually suggested for people who are found to have low levels of A1AT. This can show which variation of the A1AT faulty gene a person has. It can therefore show how severely affected they are likely to be.
Because A1AT deficiency runs in families, if a person is found to have A1AT deficiency, other family members should also be tested.
Various other tests may be suggested to determine how severely a person is affected. They may be repeated at intervals to monitor the progression of the disease. Tests may include:
- Lung function tests – these are tests to look at how well the lungs work. Spirometry is the most common of the lung function tests. It measures the amount (volume) and/or speed (flow) of air that can be inhaled and exhaled. For further details, see separate leaflet Spirometry.
- Chest X-ray – emphysema produces typical changes on chest X-ray.
- CT scan of the chest – this may be suggested to get further information on how severely the lungs are affected.
- Blood tests to see how well the liver is working.
Who gets Alpha-1 lung or liver disease?
Alpha-1 has been identified in nearly all populations and ethnic groups. It is estimated that about 1 in every 2,500 Americans have Alpha-1.
People with Alpha-1 may remain healthy throughout their lives. Early diagnosis and avoiding risk factors, such as cigarette smoking, can help prevent Alpha-1 from causing disease.
An estimated 19 million people in the United States have one normal and one defective alpha-1 gene. People with one normal gene and one defective gene (for example MZ) are called “carriers”. Carriers may pass the defective gene on to their children.
Alpha-1 can lead to lung destruction and is often first diagnosed as asthma or smoking-related Chronic Obstructive Pulmonary Disease (COPD).
Alpha-1 cannot be diagnosed by symptoms or by a medical examination alone; you need to get a simple, reliable blood test to know for sure.
Alpha-1 is the most common known genetic risk factor for emphysema.
Up to 3% of all people diagnosed with COPD may have undetected Alpha-1.
Alpha-1 can also lead to liver disease. The most serious liver diseases are cirrhosis and liver cancer.
The World Health Organization (WHO), American Thoracic Society (ATS), and the European Respiratory Society (ERS) recommend that everyone with COPD be tested for Alpha-1.
Testing for Alpha-1
The Alpha-1 Foundation supports testing for those at risk for Alpha-1. In response to concerns surrounding testing, privacy and the benefit of an early diagnosis, the Medical University of South Carolina (MUSC), with the support of the Alpha-1 Foundation, developed a free and confidential opportunity for testing.
This is a research study called the Alpha-1 Coded Testing (ACT) Study.
The Foundation also established the Alpha-1 Research Registry at MUSC to encourage research, the development of new treatments and a cure for Alpha-1. The Registry is a confidential database made up of both Alphas and Alpha-1 carriers.
The Alpha-1 Genetic Counseling Center is also located at MUSC. The genetic counselor is available to provide support and information to patients, caregivers, and healthcare professionals.
See Participate in Research Programs to learn how to participate in the ACT Study and be tested for Alpha-1; to join the Research Registry; or to learn more about the Foundation’s research programs.
What is the treatment for alpha-1 antitrypsin deficiency?
At present, there is no cure for A1AT deficiency. Most people are diagnosed with the condition after they have developed lung or liver disease. Treatment aims at slowing down the progression of the disease.
For those who develop emphysema, treatment is similar to that for COPD that is not caused by A1AT deficiency. (For further details about the treatment of COPD, see separate leaflet ‘Chronic Obstructive Pulmonary Disease’.)
Briefly, treatment for A1AT deficiency may include the following.
Smoking speeds up the development of lung disease in people with A1AT deficiency, so stopping smoking is very important.
Medication given via inhalers. The medication within the inhaler is in a powdered form which you breathe in (inhale). The medication may be:
A bronchodilator medicine. These medicines relax the muscles in the airways (bronchi) to open them up (dilate them) as widely as possible.
A steroid medicine. Steroids reduce inflammation. A steroid inhaler may not have much effect on the usual symptoms of emphysema, but may help to prevent flare-ups.
Steroid tablets. A short course of steroid tablets (called prednisolone) is sometimes prescribed during a bad flare-up of wheeze and breathlessness (often during a chest infection).
Steroids help by reducing the extra inflammation in the airways which is caused by infections.
Antibiotics. These are usually prescribed during a chest infection, or during a flare-up of symptoms which may caused by a chest infection.
Theophylline tablets. Theophylline is a bronchodilator medicine (it opens the airways) that is sometimes used.
This is an option in a very small number of cases. Sometimes large air-filled sacs (called bullae) develop in the lungs in people with COPD
. A single large bulla might be suitable for removal with an operation in some people. This can improve symptoms in some people. Lung transplantation may also be an option in some cases.
- Cutting down on alcohol. Excessive alcohol consumption should be avoided because it may hasten liver damage in someone with A1AT deficiency.
- Immunisations. Two immunisations are advised for people with emphysema:
- A yearly flu jab each autumn protects against possible influenza and any chest infection that may develop due to this.
- Immunisation against pneumococcus (a germ that can cause serious chest infections). This is a one-off injection and not yearly like the flu jab.
- Pulmonary rehabilitation programmes. These are programmes that provide education and advice about living with emphysema and COPD, as well as psychological support as needed.
Studies have shown that people with COPD who exercise regularly tend to improve their breathing, ease their symptoms, and have a better quality of life.
So these programmes also include exercises and advice to try to help a person to stay as fit as possible.
Home oxygen therapy. Some people with very severe emphysema due to A1AT deficiency may benefit from this.
Oxygen can be given with a face mask or through little tubes (nasal cannulae or nasal specs) that sit just under the nostrils.
Portable oxygen is available in cylinders but, if someone needs long-term oxygen therapy (LTOT), for long periods of the day, an oxygen concentrator is required.
This is a big machine (about two feet square and two and a half feet tall) that plugs into a normal electrical socket.
The concentrator takes oxygen from the air in the room, and concentrates it, meaning that it is separated from other gases in air, so the person only has pure oxygen to breathe in.
Intravenous alpha-1 antitrypsin deficiency replacement
It is possible to treat people with A1AT deficiency by giving them the A1AT that they are lacking in their bloodstream, in medicine-form. It can be given intravenously (into a vein).
However, there is a question about the benefits of this treatment. There are no well-designed research studies that have absolutely proven that giving this treatment helps to improve survival or slow down the rate of progression of the lung disease.
The National Institute for Health and Clinical Excellence (NICE) in the UK does not recommend treatment by replacing A1AT at present due to the lack of evidence for its benefit.
However, this decision has been criticised by some people. The medicine is available and is used in some other countries.
What is the prognosis (outlook)?
Because different people with A1AT deficiency can have different degrees of symptoms, and because the disease progresses more slowly in some people and more quickly in others, the prognosis (outlook) is very variable.
Some people with A1AT deficiency may just have mild wheezing and mild shortness of breath in their 70s, whilst others may have severe lung disease in their 20s or 30s.
Although there is no cure for A1AT deficiency, early diagnosis and treatment can help to slow down the rate of progression of the disease.
And, with regular monitoring and careful management of their condition, many people with A1AT deficiency can stay well and healthy.