Alpha-1 antitrypsin deficiency is an inherited genetic condition. A genetic condition is one that can be passed on from parents through genes. In alpha-1 antitrypsin deficiency the result of a genetic abnormality leads to lung and, in some people, liver damage.
Lung symptoms are the most common and include shortness of breath, cough and wheezing. Symptoms can worsen over time. At present, there is no cure for alpha-1 antitrypsin deficiency. Treatment aims at slowing down the progression of the disease.
What is alpha-1 antitrypsin?
Alpha-1 antitrypsin (A1AT) is a protein made by cells in the liver. It passes from the liver into the bloodstream and can travel to the lungs. Its main function is to protect the lungs from damage caused by other types of proteins called enzymes.
Enzymes are essential for the normal working and development of the body. In the lungs, certain enzymes called proteases help to fight infection, by removing germs (bacteria),and may also be released to try to protect the lungs from tobacco smoke. However, the activity of these protease enzymes needs to be balanced.
If the balance tips and there is too much activity, lung tissue can start to become damaged by the enzymes. A1AT helps to balance the protease enzymes in the lungs and stop lung damage.
What is alpha-1 antitrypsin deficiency?
A1AT deficiency is an inherited genetic condition. A genetic condition is one that can be passed on from parents through genes. It was first described in 1963 by Dr Sten Eriksson, a Danish doctor.
In the centre (nucleus) of most cells in the body there are 46 chromosomes arranged in 23 pairs. One chromosome from each pair comes from a person's mother and one from a person's father. Chromosomes are made of DNA.
DNA stands for deoxyribonucleic acid and forms a person's genetic material. A gene is the basic unit of this genetic material. It is made up of a sequence (or piece) of DNA and sits at a particular place on a chromosome. So, a gene is a small section of a chromosome. Each gene controls a particular feature or has a particular function in the body.
Someone with A1AT deficiency has a fault in a gene on chromosome number 14. This fault means that they still make A1AT but it is mis-shaped. It gets stuck in their liver and cannot pass out into their bloodstream and so to their lungs. This can lead to lung damage and, in some people, liver damage.
There is not enough A1AT in their lungs to balance the protease enzymes and to protect their lungs from enzyme damage. The walls of the small air sacs in their lungs (the alveoli) can start to become damaged and destroyed by the enzymes, leading to a condition called emphysema.
The alveoli normally have a good blood supply; oxygen from the air that a person breathes in is transferred into their bloodstream from the alveoli. If the alveoli are damaged (as in emphysema), this oxygen transfer becomes affected.
In some people, because the abnormal A1AT gets stuck in the liver, it may also damage liver cells, causing scarring and liver disease. However, not everyone with A1AT deficiency develops liver disease.
There are more than 100 variants of A1AT but only a handful have the ability to cause A1AT deficiency. The normal A1AT allele (form of the gene) is called M; the 2 most common A1AT alleles causing deficiency are S and Z. With the S allele, there is normally enough A1AT to protect the lungs (about 80% of normal levels) but there is a higher risk of emphysema if they smoke or are exposed to other environmental risk factors. With the Z allele, there is a significantly higher rate of both emphysema and liver disease.
Emphysema is one of the lung conditions that comes under the general term chronic obstructive pulmonary disease (COPD). COPD includes the conditions chronic bronchitis and emphysema. (Chronic means persistent and bronchitis is inflammation of the bronchi - the airways of the lungs.) Someone with COPD may have chronic bronchitis, or emphysema, or both.
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 a person just inherits one copy of the faulty gene from one of their parents, they do not develop A1AT deficiency. However, recent evidence has shown that there is a slightly increased risk of liver and lung disease.
They can still make enough normal A1AT to protect their lungs from damage. However, they are a carrier of A1AT deficiency - they can pass on the faulty gene to any of their children.
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 produce the least amount of normal A1AT and are most severely affected.
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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 30 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. However, the shortness of breath can gradually become 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.
Rarely, a baby with A1AT deficiency can develop yellowing of their skin and the whites of the eyes (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 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. See the separate leaflet called Spirometry for more details.
- Chest X-ray - emphysema produces typical changes on chest X-ray.
- Computerised tomography (CT) scan of the chest - this may be suggested to obtain further information on how severely the lungs are affected.
- Blood tests to see how well the liver is working.
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. See the separate leaflet called Chronic Obstructive Pulmonary Disease for more details.
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; however, it may help to prevent flare-ups.
- Steroid tablets. A short course of steroid tablets (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 be caused by a chest infection.
- Theophylline tablets. Theophylline is a bronchodilator medicine 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:
- 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 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 A1AT 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 into a vein (intravenously).
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 Care 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 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 outlook (prognosis) 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. With regular monitoring and careful management of their condition, many people with A1AT deficiency can stay well and healthy.
Further reading and references
Chotirmall SH, Al-Alawi M, McEnery T, et al; Alpha-1 proteinase inhibitors for the treatment of alpha-1 antitrypsin deficiency: safety, tolerability, and patient outcomes. Ther Clin Risk Manag. 2015 Jan 2911:143-51. doi: 10.2147/TCRM.S51474. eCollection 2015.
Gotzsche PC, Johansen HK; Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung disease. Cochrane Database Syst Rev. 2010 Jul 7(7):CD007851.
Kok KF, Wahab PJ, Houwen RH, et al; Heterozygous alpha-I antitrypsin deficiency as a co-factor in the development of chronic liver disease: a review. Neth J Med. 2007 May65(5):160-6.
Lascano JE, Campos MA; The important role of primary care providers in the detection of alpha-1 antitrypsin deficiency. Postgrad Med. 2017 Nov129(8):889-895. doi: 10.1080/00325481.2017.1381539. Epub 2017 Oct 5.
Chronic Obstructive Pulmonary Disease; NICE Guidance (December 2018 - last updated 2019)