Alpha-1 antitrypsin deficiency – Diagnostics – Overview of Information and Clinical Research

Alpha-1 antitrypsin deficiency is a genetic condition that can damage your lungs and liver. Early diagnosis is essential, as it helps people take steps to protect their organs and slow disease progression. Simple blood tests and genetic screening can identify this inherited disorder, allowing patients to receive proper treatment and make informed lifestyle choices. Understanding who should be tested and what the diagnostic process involves can make all the difference in managing this lifelong condition.

Introduction: Who Should Be Tested and When

Alpha-1 antitrypsin deficiency, often simply called Alpha-1, is a genetic disorder that many people live with without knowing. This condition occurs when your body does not make enough of a protective protein called alpha-1 antitrypsin (AAT), which shields your lungs from damage. Without sufficient AAT, your lungs become vulnerable to destruction, particularly from inflammation and irritating substances you breathe in. The liver can also be affected, as abnormal AAT protein may build up there and cause scarring over time.^[1]

Testing for Alpha-1 is especially important for certain groups of people. Your healthcare provider may recommend diagnostic testing if you develop symptoms that suggest lung or liver problems, such as shortness of breath, wheezing, chronic cough with mucus, or repeated chest infections. These symptoms often begin between the ages of 20 and 50, though they can appear earlier or later depending on the individual and their lifestyle choices.^[3]

People who have chronic obstructive pulmonary disease (COPD) or emphysema should also consider testing, especially if these conditions appeared before age 55. Many individuals with Alpha-1 are initially misdiagnosed with asthma or regular COPD, and the underlying genetic cause is never discovered. This is unfortunate, because knowing you have Alpha-1 can change the course of your treatment and help you make better decisions about your health.^[2]

Family history matters greatly with Alpha-1. If you have a parent, sibling, or child diagnosed with this condition, you should seek testing even if you feel perfectly healthy. Alpha-1 runs in families because it is an inherited disorder caused by changes in the SERPINA1 gene. If one of your close relatives has the condition, you may be a carrier or may have inherited two abnormal copies of the gene, putting you at higher risk for lung and liver disease.^[3]

Babies can also be tested for Alpha-1 if they show signs of liver disease shortly after birth. Jaundice, which causes yellowing of the skin and eyes, or abnormal liver enzyme levels in blood tests may prompt a doctor to check for Alpha-1. About 10 percent of infants with this genetic deficiency develop liver problems, which can be serious if not identified early.^[6]

⚠️ Important

Many people with Alpha-1 antitrypsin deficiency remain undiagnosed for years, sometimes decades. Studies suggest that diagnosis is often delayed by more than five years after lung symptoms first appear. Early testing is crucial, particularly for those with unexplained breathing problems or a family history of the condition, because it allows for timely interventions that can slow disease progression and improve quality of life.

Diagnostic Methods for Alpha-1 Antitrypsin Deficiency

Diagnosing Alpha-1 antitrypsin deficiency involves several steps, starting with simple blood tests and sometimes progressing to more detailed genetic analysis. The process is designed to measure how much AAT protein is in your blood, identify the specific type of genetic changes you carry, and assess any damage that may have already occurred to your lungs or liver.^[12]

Blood Test for AAT Protein Levels

The first and most common test for Alpha-1 is a blood test that measures the level of alpha-1 antitrypsin protein circulating in your bloodstream. This test is straightforward and requires only a small sample of blood drawn from your arm. If the level of AAT in your blood is lower than normal, it suggests that you may have Alpha-1 deficiency. Normal levels of AAT help protect your lungs, so finding a reduced amount is an important clue that something is wrong.^[3]

However, a low AAT level alone is not enough to confirm the diagnosis. Other conditions or situations, such as acute inflammation or infection, can temporarily affect AAT levels. Therefore, if your initial blood test shows low AAT, your doctor will typically recommend further testing to confirm the diagnosis and understand exactly which genetic changes are responsible.^[15]

Genetic Testing: Genotype and Phenotype Tests

Genetic testing is the most reliable way to diagnose Alpha-1 antitrypsin deficiency. Once a blood test shows low AAT levels, your healthcare provider will likely order genetic tests to identify the specific variants in the SERPINA1 gene that are causing the problem. There are two main types of genetic tests used for this purpose.^[3]

A genotype test looks for the most common genetic changes known to cause Alpha-1. These changes are often referred to by letters, such as M, S, and Z. The M version of the gene is normal and produces healthy amounts of AAT. The Z and S versions are abnormal and lead to reduced or dysfunctional AAT protein. People who inherit two Z genes (ZZ) have the most severe form of Alpha-1 and are at the highest risk for lung and liver disease. Those with one Z gene and one S gene (SZ) or two S genes (SS) may have milder deficiency.^[6]

A phenotype test examines the actual type of AAT protein in your blood, rather than just looking at the gene itself. This test can detect rarer forms of Alpha-1 that might be missed by genotype testing. Both types of tests are valuable, and your doctor may recommend one or both depending on your situation. Genetic counseling is often suggested alongside genetic testing, as a counselor can help you understand what your test results mean for you and your family members.^[12]

Lung Function Tests

Once Alpha-1 is diagnosed, or if it is strongly suspected, your doctor will want to assess how well your lungs are functioning. Lung function tests, also called pulmonary function tests, measure how much air you can breathe in and out, and how quickly you can move air through your lungs. The most common lung function test is called spirometry.^[12]

During spirometry, you breathe into a tube connected to a machine that records the volume and speed of your breaths. This test helps doctors understand if your lungs have been damaged by emphysema or other lung diseases associated with Alpha-1. If you already have COPD, your doctor may perform spirometry regularly to track how your lung function changes over time.^[12]

Imaging Tests

Imaging tests allow doctors to see inside your body and look for signs of lung or liver damage. A chest X-ray is often one of the first imaging tests performed if you have breathing symptoms. It can show changes in the lungs that suggest emphysema, though it may not detect early or mild disease.^[12]

A computed tomography (CT) scan provides much more detailed images than a standard X-ray. A CT scan of the chest can reveal damage to the air sacs in your lungs (alveoli) that occurs with emphysema. Your healthcare provider may recommend a CT scan if you are newly diagnosed with Alpha-1 and have lung symptoms, or if you have emphysema and need a closer look at the extent of the damage. CT scans are also used to monitor disease progression over time.^[12]

For the liver, imaging tests such as ultrasound or CT scans can help assess whether abnormal AAT protein has built up and caused scarring or other damage. These tests are painless and use sound waves or X-rays to create pictures of your liver and surrounding organs.^[12]

Liver Function Tests

Since Alpha-1 can affect the liver as well as the lungs, your doctor may order blood tests to check how well your liver is working. These tests measure levels of certain enzymes and proteins in your blood that indicate liver health. Elevated levels of liver enzymes can suggest inflammation or damage. In some cases, further testing such as a liver biopsy may be needed to determine the extent of liver disease, though this is not commonly required for most patients.^[12]

⚠️ Important

Alpha-1 antitrypsin deficiency is often misdiagnosed as asthma or regular COPD. If you have been diagnosed with lung disease and are younger than 55, have never smoked, or have a family history of lung or liver problems, ask your doctor about testing for Alpha-1. Confirming the diagnosis can open the door to specific treatments and help your family members understand their own risk.

Diagnostics for Clinical Trial Qualification

Clinical trials are research studies that test new treatments or approaches for Alpha-1 antitrypsin deficiency. Participating in a clinical trial can give patients access to cutting-edge therapies that are not yet widely available. However, not everyone with Alpha-1 is eligible for every trial. Researchers use specific diagnostic tests and criteria to determine who can join a study, ensuring that participants are likely to benefit and that the trial results will be meaningful.^[14]

Confirming the Diagnosis with Genetic Testing

Before enrolling in a clinical trial, participants must have a confirmed diagnosis of Alpha-1 antitrypsin deficiency. This typically requires genetic testing to identify the specific SERPINA1 gene variants involved. Many trials focus on individuals with the most severe form of Alpha-1, such as those with two copies of the Z gene (ZZ genotype). Genetic confirmation ensures that the study participants truly have the condition being studied, which is essential for accurate results.^[14]

Measuring AAT Protein Levels

Clinical trials often require that participants have AAT protein levels below a certain threshold. This is measured through a blood test. Trials testing augmentation therapy, for example, may only enroll people whose AAT levels are significantly reduced, as these individuals are the ones who would benefit most from receiving extra AAT protein. The exact level required can vary from study to study, but it is always clearly defined in the trial’s eligibility criteria.^[14]

Assessing Lung Function

Lung function testing, especially spirometry, is a key part of qualifying for many Alpha-1 clinical trials. Researchers often look for participants who have a certain degree of lung impairment, such as reduced forced expiratory volume (the amount of air you can forcefully exhale in one second). This helps ensure that the trial includes people who are at a stage of disease where the treatment being tested could make a noticeable difference.^[14]

Some trials may also use more advanced measures of lung health, such as CT scan densitometry. This technique measures the density of lung tissue on a CT scan. As emphysema progresses, lung tissue becomes less dense because the air sacs are destroyed. Tracking changes in lung density over time can show whether a treatment is slowing the progression of the disease. Trials that use this method often require participants to have a baseline CT scan before enrollment so that future changes can be compared.^[14]

Evaluating Overall Health and Medical History

Clinical trials have strict criteria to ensure participant safety and study reliability. Beyond confirming Alpha-1 and measuring lung function, researchers will review your overall health, medical history, and current medications. Some trials may exclude people who have certain other medical conditions, such as severe heart disease or active infections. Others may require that you are not currently receiving certain treatments, like augmentation therapy, if the trial is testing a new version of that therapy.^[14]

Age and smoking history are also commonly considered. Some studies focus on people who have never smoked, while others may include current or former smokers. The goal is to create a study group that will provide clear answers about whether the new treatment works and for whom it works best.^[14]

Prognosis and Survival Rate

Prognosis

The outlook for people with Alpha-1 antitrypsin deficiency varies widely and depends on several factors, including the specific genetic variant, lifestyle choices, and access to treatment. Not everyone with Alpha-1 develops serious health problems. Some people, especially those who have only one abnormal copy of the gene and never smoke, may live a completely normal lifespan with little to no symptoms. Others, particularly those with two copies of the Z gene (ZZ genotype) and those who smoke, are at much higher risk for developing emphysema and liver disease.^[1]

About 75 percent of people with two malfunctioning genes will eventually develop problems with lung function. Lung symptoms, such as shortness of breath, wheezing, and chronic cough, typically begin to appear between the ages of 30 and 50. Smoking dramatically accelerates the progression of lung damage in people with Alpha-1, making it the single most important risk factor. People who smoke and have Alpha-1 tend to develop emphysema much earlier and experience faster decline in lung function compared to nonsmokers with the condition.^[1]

Liver disease is less common but still a significant concern. About 10 percent of infants and 15 percent of adults with Alpha-1 develop liver damage, which can progress to cirrhosis (scarring of the liver). In severe cases, liver transplantation may be needed. The liver problems occur because abnormal AAT protein builds up in the liver instead of being released into the bloodstream, causing damage over time.^[11]

The good news is that many people with Alpha-1 can take steps to improve their prognosis. Avoiding smoking and exposure to secondhand smoke, staying up to date with vaccinations for flu and pneumonia, and seeking early treatment for respiratory infections can all help protect the lungs. Augmentation therapy, a treatment that supplies the body with additional AAT protein, may also slow the progression of lung disease in people with emphysema.^[9]

Survival Rate

Life expectancy for people with Alpha-1 antitrypsin deficiency is heavily influenced by whether or not they smoke. For those who smoke, the average life expectancy is around 50 years. This is because smoking accelerates lung damage and increases the risk of severe emphysema at a relatively young age. In contrast, people with Alpha-1 who do not smoke often have a nearly normal life expectancy. Many can live into their 60s, 70s, or beyond, especially if they take good care of their health and avoid environmental pollutants.^[8]

It is important to note that these are general estimates, and individual outcomes can vary. Some people with Alpha-1 who never smoked may still develop lung disease, though it typically progresses more slowly than in smokers. Access to medical care, early diagnosis, and treatments such as augmentation therapy and pulmonary rehabilitation can all improve outcomes and extend life expectancy.^[1]

For individuals with severe lung disease, lung transplantation may be an option. This major surgery involves replacing one or both damaged lungs with healthy lungs from a donor. While lung transplantation carries risks, it can significantly improve quality of life and survival for people with advanced emphysema caused by Alpha-1. Similarly, for those with severe liver disease, liver transplantation may be lifesaving.^[13]

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Alpha-1 antitrypsin deficiency – Diagnostics

Introduction: Who Should Be Tested and When