What is Alpha-1 Antitrypsin Mutation?
Alpha-1 antitrypsin is a protective substance made mostly in the liver. It’s job is to control the activity of certain enzymes in the white blood cells (neutrophils) within the lungs. This control helps shield the lungs from damage that could be caused by these enzymes. These enzymes, known as elastases, are responsible for nearly 90% of the harm done to the air passages in our lungs caused by these enzymes when uncontrolled.
If these elastase enzymes aren’t properly managed, they can damage a type of lung tissue, which increases the chances of developing a lung disease known as chronic obstructive pulmonary disease (COPD). However, if your body generates versions of this protective substance that don’t function properly, they can build up in your liver cells. This abnormal accumulation can lead to liver disease, as the built-up substances can become toxic. Therefore, maintaining the proper balance and functioning of these substances is essential for lung and liver health.
What Causes Alpha-1 Antitrypsin Mutation?
Alpha-1 antitrypsin deficiency is a condition that is caused by changes in your genes, specifically within a group called the “serpin” genes. The way this condition is inherited is somewhat complex – not like a light switch that simply turns on or off. Some people with this condition will carry two copies of the changed gene (we call this “homozygous”), while some might just carry one (this is “heterozygous”). The gene named SERPINA1, found on chromosome 14, is involved in this process.
Scientists have a way of clasifying these genetic changes. The most common version, which carries out its intended function, is designated as M. So, someone with two ‘normal’ copies of the gene would be classified as PI*MM. However, there are other versions that can interfere with the gene’s function. These are called Z and S, but there are other rare versions as well like I, M, and some with no function at all, dubbed “null”.
To identify these different versions, a process called a Polymerase Chain Reaction (or PCR for short) is used. This can pick out specific DNA sequences that mark these different versions. Out of all these versions, the PI*Z version tends to be most common in cases of severe alpha-1 antitrypsin deficiency. This version has a slight change – an exchange of one amino acid for another at a certain spot on the protein molecule this gene makes. This tiny change causes the proteins to stick together in the liver cells, while also weakening their ability to control a certain enzyme in the lungs.
There’s also the PI*S version, the other common version, which also involves an amino acid exchange. But unlike the Z version, it does not increase the risk of liver disease. Someone carrying two copies of the S version generally won’t develop lung disease. However, those who carry one S and one Z version may be at an elevated risk of developing chronic obstructive pulmonary disease (COPD) – especially if their alpha-1 antitrypsin levels are low or if they are smokers.
Risk Factors and Frequency for Alpha-1 Antitrypsin Mutation
Research has found that the most frequent deficiency allele, or gene variant, linked to alpha-1 antitrypsin deficiency (AATD) is PI*Z. This is especially common in North and West Europe. On the other hand, the PI*S allele variants are more common in Southern Europe. However, these gene variants are not very common in the overall world population; PI*ZZ only makes up 0.1% and PI*SZ only represents about 0.7%.
Despite the consistent presence of these variants, AATD is often not diagnosed. In fact, less than 10% of predicted cases are actually reported in the United States. This suggests that a lot of people have the disease but don’t know it. In cases where the disease is diagnosed, the average age at diagnosis is 41.3 years. Just like with other less common diseases, it typically takes a while and requires multiple doctors before the condition is correctly identified.
Signs and Symptoms of Alpha-1 Antitrypsin Mutation
Alpha-1 antitrypsin deficiency, often referred to as AATD, is a condition that can lead to a variety of health problems. It is primarily known for causing chronic obstructive pulmonary disease (COPD), liver issues, and inflammation of fatty tissue under the skin, also known as panniculitis. Some studies have linked AATD to kidney inflammation, known as glomerulonephritis, and certain types of cancer. There are also cases where AATD is connected with celiac disease, an unusual state of blood vessels called fibromuscular dysplasia, and inflammation of the pancreas, or pancreatitis. Interestingly, around 15% of patients with granulomatosis with polyangiitis, a rare form of inflammation of blood vessels, have a type of AATD known as the ZZ genotype.
Pulmonary issues related to AATD resemble COPD caused by other factors but tend to show some unique traits. These include an early onset of symptoms, usually in a person’s 30s or 40s, and a specific pattern observed in CT scans where the areas of swelled lung tissue, known as emphysema, are mainly located at the base of the lungs. Still, symptoms might not be noticeable until later, and this pattern can change, making AATD sometimes look identical to COPD caused by other factors. Symptoms include breathlessness, coughing, wheezing, and frequent upper respiratory tract infections. Risk factors such as smoking, exposure to smoke from burning organic materials, and respiratory infections can worsen these pulmonary symptoms by increasing destructive protein activity in white blood cells called neutrophils. Over time, this can lead to the destruction of lung tissue and develop into COPD.
Outside the lungs, the accumulation of the ZZ protein, a characteristic of AATD, can cause significant health problems. These issues can include hepatitis in children, liver cirrhosis in adults, and an increased risk of liver cell cancer. Early in a person’s life, infants may show signs of hepatitis, making AATD the second leading cause of liver transplants in children. As these children grow, liver inflammation can decrease, only to return in adults, potentially leading to cirrhosis—all of which is typically subclinical, meaning it doesn’t result in noticeable symptoms. In a small number of adults, this condition can progress to liver failure, requiring a liver transplant. Panniculitis, a rare inflammation of fatty tissue under the skin, can occur in one out of every 1,000 cases of the ZZ genotype.
Testing for Alpha-1 Antitrypsin Mutation
The American Thoracic Society and the European Respiratory Society recommend screening for alpha-1 antitrypsin deficiency in certain people. This deficiency can be found in those with Chronic Obstructive Pulmonary Disease (COPD), adults and teenagers who have asthma that doesn’t respond to treatment, and those with unexplained liver damage or disease. Alpha-1 antitrypsin is a protein that protects your lungs and liver from damage, so a deficiency can lead to problems.
To test for this deficiency, doctors initially measure the levels of alpha-1 antitrypsin in the blood through a simple blood test. If the test shows low levels of this protein, the patient may then undergo genotyping. Genotyping is a type of genetic test that can determine the specific type (genotype) of the alpha-1 antitrypsin genes a person has inherited. If the results from the genotyping and the serum level test don’t match up, the diagnosis can be confirmed with a more specific analysis or phenotyping (looking at how the genes are actually functioning).
They also suggest getting chest X-rays and chest CT scans to visualize any damage in the lung that may be caused by this condition, evident in features such as enlarged airspaces. Pulmonary function tests, which measure how well your lungs work, are also required. These tests can help detect a decrease in your ability to blow air out quickly – a common sign of this disorder.
Treatment Options for Alpha-1 Antitrypsin Mutation
For people with alpha-1 antitrypsin deficiency, it’s important to avoid anything that causes too much activity in a type of white blood cell called neutrophils. This includes smoking and infections. There are several vaccines that can help prevent infections, including the pneumococcal polysaccharide, influenza, protein conjugate pneumococcal, and tetanus-diphtheria-pertussis vaccines.
Patients typically use inhalers that are designed to help with the symptoms of Chronic Pulmonary Disease (COPD), a type of lung disease. Corticosteroids, a type of medication that helps reduce inflammation, should only be used by those patients who show frequent signs of their condition getting worse despite regular usage of conventional inhalers. Sometimes rehabilitation, oxygen therapy, or even lung transplants, may be needed, depending on the individual case.
Another form of treatment is called augmentation therapy, which supports but does not replace the typical COPD therapies. Augmentation therapy involves introducing purified human plasma alpha-1 antitrypsin into the body via injection on a weekly basis to maintain the adequate levels of Antitrypsin that helps protect the lungs from damage. However, this approach is only suitable for patients with both a severe deficiency of alpha-1 antitrypsin and COPD. Potential side-effects are rare, but can include headaches, nausea, dizziness, and in very rare cases, anaphylaxis (a severe allergic reaction).
Lung transplants for alpha-1 antitrypsin deficiency patients are not yet fully established due to lack of data. However, those with severe COPD (lung function consistently measured below 30% of normal) seem to have increased survival times if they undergo a transplant. The impact of a liver transplant on lung disease progression has not been determined yet, so it’s unclear whether augmentation should take place after this type of transplant.
Looking to the future, inhalation therapy (which targets a specific organ and reduces the alpha-1 protein amounts needed) and gene therapy (which has the potential to provide constant levels of alpha-1 antitrypsin with a single administration) might offer paths to simplify and make the treatment more effective. Research is also being done on the viability of using human-made alpha-1 proteins as a treatment instead of using those derived from human plasma.
What else can Alpha-1 Antitrypsin Mutation be?
When doctors are trying to diagnose if someone has the alpha-1 antitrypsin mutation, they will also consider these possible conditions:
- Autoimmune hepatitis (a disease where the body’s immune system attacks the liver)
- Bronchiectasis (a condition where the airways in the lungs widen and become damaged)
- Bronchitis (inflammation of the bronchial tubes in the lungs)
- COPD (Chronic Obstructive Pulmonary Disease, a long-term lung condition)
- Cystic fibrosis (a genetic disease that causes severe damage to the lungs and digestive system)
- Emphysema (a lung condition that causes shortness of breath)
- Kartagener syndrome (a rare genetic disorder that affects the respiratory tract)
- Viral hepatitis (an infection that causes liver inflammation)
