Alpha-1 Antitrypsin Deficiency: Gene Mutation, Symptoms, Treatment, and Life Expectancy

Alpha-1 antitrypsin deficiency occurs worldwide, but its prevalence varies by population. This disorder affects about 1 in 1,500 to 3,500 individuals with European ancestry. It is uncommon in people of Asian descent. Many individuals with alpha-1 antitrypsin deficiency are likely undiagnosed, particularly people with a lung condition called chronic obstructive pulmonary disease (COPD). COPD can be caused by alpha-1 antitrypsin deficiency; however, the alpha-1 antitrypsin deficiency is often never diagnosed. Some people with alpha-1 antitrypsin deficiency are misdiagnosed with asthma.

Mutations in the SERPINA1 gene cause alpha-1 antitrypsin deficiency.

The SERPINA1 gene provides instructions for making a protein called alpha-1 antitrypsin. This protein protects the body from being damaged by a powerful enzyme called neutrophil elastase. Neutrophil elastase is released from white blood cells to fight infection, but it can attack normal tissues (such as lung tissue) if not carefully controlled by alpha-1 antitrypsin. Mutations in the SERPINA1 gene can lead to a shortage (deficiency) of alpha-1 antitrypsin protein or an abnormal form of the protein that cannot control neutrophil elastase. Uncontrolled, neutrophil elastase destroys alveoli, which can lead to emphysema. The abnormal form of alpha-1 antitrypsin can also accumulate in the liver and may damage this organ.

AATD may first be suspected in people with evidence of liver disease at any age, or lung disease (such as emphysema), especially when there is no obvious cause or it is diagnosed at a younger age.

Confirming the diagnosis involves a blood test showing a low serum concentration of the alpha-1 antitrypsin (AAT) protein, and either:

• detecting a functionally deficient AAT protein variant by isoelectric focusing (a method for detecting mutations); or
• detecting SERPINA1 gene mutations on both copies of the gene with molecular genetic testing. (This confirms the diagnosis when the above-mentioned tests are not performed or their results are not in agreement.)[3]

Specialists involved in the diagnosis may include primary care doctors, pulmonologists (lung specialists), and/or hepatologists (liver specialists).[4]

Treatment of alpha-1 antitrypsin deficiency (AATD) depends on the symptoms and severity in each person. COPD and other related lung diseases are typically treated with standard therapy.[3][4] Bronchodilators and inhaled steroids can help open the airways and make breathing easier.[4]

Intravenous augmentation therapy (regular infusion of purified, human AAT to increase AAT concentrations) has been recommended for people with established fixed airflow obstruction (determined by a specific lung function test).[3] This therapy raises the level of the AAT protein in the blood and lungs.[4]

Lung transplantation may be an appropriate option for people with end-stage lung disease. Liver transplantation is the definitive treatment for advanced liver disease.[3]

When present, panniculitis may resolve on its own or after dapsone or doxycycline therapy. When this therapy does not help, it has responded to intravenous augmentation therapy in higher than usual doses.[3]

All people with severe AATD should have pulmonary function tests every 6 to 12 months. Those with ATT serum concentrations 10% to 20% of normal should have periodic evaluation of liver function to detect liver disease. People with established liver disease should have periodic ultrasounds of the liver to monitor for fibrotic changes and liver cancer (hepatocellular carcinoma).[3]

Yearly vaccinations against influenza and pneumococcus are recommended to lessen the progression of lung disease. Vaccination against hepatitis A and B is recommended to lessen the risk of liver disease. People with AATD should avoid smoking and occupations with exposure to environmental pollutants.[3]

Parents, older and younger siblings, and children of a person with severe AATD should be evaluated to identify as early as possible those who would benefit from treatment and preventive measures.[3]

• GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
• Orphanet Emergency Guidelines is an article which is expert-authored and peer-reviewed that is intended to guide health care professionals in emergency situations involving this condition

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

Alpha1-Proteinase Inhibitor (Human) (Brand name: Prolastin) - Manufactured by Grifols United States: FDA-approved indication: For chronic replacement therapy of individuals having congenital deficiency of alpha1- proteinase inhibitor with clinically demonstrable panacinar emphysema.