Alpha-1 Antitrypsin Deficiency (AATD): What is it? What are the symptoms? How is it diagnosed? How is it treated?

Alpha-1 Antitrypsin Deficiency (AATD) is a rare genetic condition that can lead to severe lung and liver disease. It is caused when the body does not make adequate alpha-1 antitrypsin (AAT) protein, which helps protect the lungs from damage.

Individuals who don’t have sufficient levels of AAT are more susceptible to emphysema, chronic obstructive pulmonary disease (COPD), cirrhosis of the liver, and potentially liver cancer.

What Is Alpha-1 Antitrypsin?

Alpha-1 antitrypsin is a protein that the liver produces to ward off lung inflammation, which can be triggered by infections and irritants such as cigarette smoke. The SERPINA1 gene produces this protein. If this gene is altered (mutated), reduced or defective AAT protein can be made, causing alpha-1 antitrypsin deficiency.

Causes of AATD

AATD results from disease-causing mutations in the SERPINA1 gene encoding the AAT protein. These mutations can lead to:

• Deficiency or absence of AAT in the blood
• A malfunctioning AAT protein
• Accumulation of protein in the liver resulting in liver damage

External factors such as smoking, pollution, and exposure to chemicals can exacerbate symptoms and hasten lung deterioration.

Inheritance Pattern

Alpha-1 Antitrypsin Deficiency has an autosomal codominant mode of inheritance:

• The M allele represents the standard form of the gene.
• Very low levels of AAT are produced by the Z allele.
• The S allele results in a more moderate decline.

Common Genetic Combinations:

• MM: Normal
• MZ: Slightly elevated chance of liver/lung problems
• ZZ: Severe risk profile for AATD-associated complications
• SZ: Higher risk, particularly if exposed to smoke

How is Alpha-1 Antitrypsin Deficiency Diagnosed and Evaluated?

‘Breathing’ Symptoms (usually 20–50 years old):

• Dyspnea on mild exertion
• Wheezing and chronic cough
• Repeated infections of the respiratory system
• Reduced exercise capacity
• Tiredness and heart racing on standing
• Barrel chest (indicates emphysema)

Liver-Related Symptoms:

• Yellow skin and eyes, which is also known as jaundice
• Belly, feet, or legs are puffy or swollen
• Cirrhosis and liver scarring
• Hepatocellular carcinoma risk (liver cancer risk)

Rare Symptoms:

• Panniculitis – painful, reddened skin lumps or patches

Who Is at Risk?

It is most prevalent in persons of European descent, with an incidence rate of 1 in 1,500 to 3,500 people. It is rare in Asians and can be easily overlooked. It is often misdiagnosed as asthma or COPD with no AATD testing.

Diagnosis

To diagnose AATD, your doctor might suggest:

• Blood testing to measure AAT protein levels
• Germline molecular genetic testing for the SERPINA1 mutations
• Pulmonary function tests as measures of lung function
• Measurements of liver function and imaging (such as a CT scan)

An early diagnosis is essential in the treatment and prevention of severe sequelae.

Therapeutic strategies for alpha-1 antitrypsin deficiency

1. AAT Augmentation Therapy

• Intravenous infusions of highly purified human AAT protein raise blood levels and shield the lungs from damage

2. Medications

• Bronchodilators and steroids are inhaled to open up the airways for easier breathing
• Antibiotics to ward off respiratory infections
• Antioxidants (Vitamins A, C, and E) and N-acetylcysteine as supplementation

3. Surgical Treatments

• Lung volume reduction surgery
• Lung transplantation for end-stage lung disease
• Liver transplantation, which restores normal AAT levels

4. Lifestyle Recommendations

• Avoid smoking and alcohol.
• Vaccinate: Prevention is MUCH better than treatment – get vaccinated for flu, hepatitis A and B, and pneumococcal infections

Investigational and Future Therapies

New treatments for AATD are currently under investigation, including:

• Gene therapy to correct the mutated SERPINA1 gene
• AAT nasal sprays
• Synthetic inhibitors of neutrophil elastase
• Drugs such as rapamycin and carbamazepine increase AAT expression and reduce liver damage

Augmentation Therapy Criteria

Such treatment is commonly administered to people who:

• Are 18 years or older
• Have AAT levels less than 11 μmol/L
• Show airway obstruction on spirometry
• Are not smokers or have not smoked for the past 6 months
• Do not have IgA deficiency
• Agree to accept infusions at a hospital

Living with AATD

Alpha-1 antitrypsin deficiency needs to be managed lifelong. Satisfactory medical care, genetic counseling, and support groups are important. Regular lung and liver follow-up is advised for patients to maintain their healthy lifestyle and stay up-to-date with available treatment options.

Support and Resources

Learn More

For complete information about Alpha-1 Antitrypsin Deficiency, please go to:

National Heart, Lung, and Blood Institute (NHLBI)

Online Mendelian Inheritance in Man (OMIM)

Orphanet – The portal for rare diseases and orphan drugs

Stay Informed & Protected!

If you or a family member has unexplained lung or liver problems, consider asking your doctor about being tested for Alpha-1 Antitrypsin Deficiency.

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