What Is Alpha-1 Antitrypsin Deficiency?

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A1AT Deficiency

Alpha-1 antitrypsin deficiency is an inherited disorder that may cause lung disease and liver disease. The signs and symptoms of the condition and the age at which they appear vary among individuals.

People with alpha-1 antitrypsin deficiency usually develop the first signs and symptoms of lung disease between ages 20 and 50. The earliest symptoms are shortness of breath following mild activity, reduced ability to exercise, and wheezing.

Other signs and symptoms can include unintentional weight loss, recurring respiratory infections, fatigue, and rapid heartbeat upon standing. Affected individuals often develop emphysema, which is a lung disease caused by damage to the small air sacs in the lungs (alveoli). Characteristic features of emphysema include difficulty breathing, a hacking cough, and a barrel-shaped chest. Smoking or exposure to tobacco smoke accelerates the appearance of emphysema symptoms and damage to the lungs.

About 10 percent of infants with alpha-1 antitrypsin deficiency develop liver disease, which often causes yellowing of the skin and whites of the eyes (jaundice). Approximately 15 percent of adults with alpha-1 antitrypsin deficiency develop liver damage (cirrhosis) due to the formation of scar tissue in the liver. Signs of cirrhosis include a swollen abdomen, swollen feet or legs, and jaundice. Individuals with alpha-1 antitrypsin deficiency are also at risk of developing a type of liver cancer called hepatocellular carcinoma.

 

In rare cases, people with alpha-1 antitrypsin deficiency develop a skin condition called panniculitis, which is characterized by hardened skin with painful lumps or patches. Panniculitis varies in severity and can occur at any age.

Frequency

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.

Genetic Changes

Mutations in the SERPINA1 gene cause alpha-1 antitrypsin deficiency. This gene provides instructions for making a protein called alpha-1 antitrypsin, which protects the body from a powerful enzyme called neutrophil elastase. Neutrophil elastase is released from white blood cells to fight infection, but it can attack normal tissues (especially the lungs) if not tightly controlled by alpha-1 antitrypsin.

Mutations in the SERPINA1 gene can lead to a shortage (deficiency) of alpha-1 antitrypsin or an abnormal form of the protein that cannot control neutrophil elastase. Without enough functional alpha-1 antitrypsin, neutrophil elastase destroys alveoli and causes lung disease. Abnormal alpha-1 antitrypsin can also accumulate in the liver and damage this organ.

Environmental factors, such as exposure to tobacco smoke, chemicals, and dust, likely impact the severity of alpha-1 antitrypsin deficiency.

Inheritance Pattern

This condition is inherited in an autosomal codominant pattern. Codominance means that two different versions of the gene may be active (expressed), and both versions contribute to the genetic trait.

The most common version (allele) of the SERPINA1 gene, called M, produces normal levels of alpha-1 antitrypsin. Most people in the general population have two copies of the M allele (MM) in each cell. Other versions of the SERPINA1 gene lead to reduced levels of alpha-1 antitrypsin.

For example, the S allele produces moderately low levels of this protein, and the Z allele produces very little alpha-1 antitrypsin. Individuals with two copies of the Z allele (ZZ) in each cell are likely to have alpha-1 antitrypsin deficiency. Those with the SZ combination have an increased risk of developing lung diseases (such as emphysema), particularly if they smoke.

Worldwide, it is estimated that 161 million people have one copy of the S or Z allele and one copy of the M allele in each cell (MS or MZ). Individuals with an MS (or SS) combination usually produce enough alpha-1 antitrypsin to protect the lungs. People with MZ alleles, however, have a slightly increased risk of impaired lung or liver function.

Other Names for This Condition

  • AAT
  • AATD
  • alpha-1 protease inhibitor deficiency
  • alpha-1 related emphysema
  • genetic emphysema
  • hereditary pulmonary emphysema
  • inherited emphysema

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Cause

Alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the SERPINA1 gene. This gene gives the body instructions to make a protein called alpha-1 antitrypsin (AAT), which protects the body from an enzyme called neutrophil elastase. Neutrophil elastase helps the body fight infections, but it can also attack healthy tissues (especially the lungs) if not controlled by AAT.

Mutations that cause AAT can cause a deficiency or absence of AAT, or a form of AAT that does not work well. This allows neutrophil elastase to destroy lung tissue, causing lung disease.

In addition, abnormal AAT can build up in the liver and cause damage to the liver. specially in people who have the allele ZZ (PI * ZZ) of AAT.  Liver problems do not occur in people who have the null (that result in none or almost none AAT).

The severity of AATD may also be worsened by environmental factors such as exposure to tobacco smoke, dust, and chemicals.

Treatment

The treatment is basically done by giving the enzyme alpha-1 antitrypsin (intravenous infusion of purified, human AAT) to prevent the progression of lung disease, aiming to increase the level of alpha-1 antitrypsin in the blood. Skin problems usually get better when the enzyme is given. It is recommended to avoid smoking and drinking.

Other treatments include:

  • Bronchodilators and inhaled steroids can help open the airways and make breathing easier
  • Lung volume reduction surgery
  • Lung transplantation for patients with advanced emphysema due to severe AAT deficiency
  • Liver transplantation for patients with severe liver disease. After a liver transplant the AAT deficiency is corrected, because normal donor liver produces and secretes normal AAT

Antibiotics if there are infections.

  • Vaccination against hepatitis A and B
  • Preventive vaccines against influenza and pneumococcal vaccines.
  • Ongoing research for other treatments include:
  • Gene therapy to replace the abnormal gene with a normal SERPINA1 gene (gene therapy) in the liver cells
  • Nasal spray with alpha-1 antitrypsin
  • Synthetic inhibitors of human neutrophil elastase (intravenously and orally) which theoretically could provide protection against lung damage
  • Antioxidant therapy with vitamins A, C and E and N-acetylcysteine for the treatment of emphysema
  • Medications to increase blood levels of AAT and decrease liver damage (Rapamycin and carbamazepine).
  • Treatment with purified alpha-1 antitrypsin is indicated only when individuals:
  • Are older than 18 years of age
  • Have levels of alpha-1 antitrypsin in blood that are less than 11 micromoles / liter
  • Have pulmonary function tests (spirometer ) that show airway obstruction
  • Do not smoke or have stopped smoking for at least the last 6 months
  • Are willing to be treated at the hospital
  • Do not have immunoglobulin A deficiency (because the therapy with alpha-1 may contain traces of immunoglobulin type A (IgA), and patients with IgA deficiency may have antibodies against IgA)
  • In some cases it is also done in people who have normal airflow but who have a CT scan that shows emphysema in the lung.

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures.

They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Living With

Living with a genetic or rare disease can impact the daily lives of patients and families. These resources can help families navigate various aspects of living with a rare disease.

Healthcare Resources

Alpha-1 Foundation Genetic Counseling Center. The Call Center offers information and resources to individuals, family members and medical professionals on the genetics of Alpha-1 and provides information on testing options.

Genetics Resources

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from Genetics Home Reference.

Financial Resources

National Organization for Rare Disorders (NORD) has Disease-Specific Assistance Programs designed to help patients with out-of-pocket costs such as monthly insurance premiums or deductibles. In addition, some programs may provide financial assistance for additional expenses related to a patient’s diagnosis such as travel to see a specialist.

Patient Services, Inc (PSI) provides financial support and guidance for qualified patients with specific chronic diseases. PSI helps patients find solutions to the social and economic problems confronting patients with chronic conditions.

Learn More

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

Genetics Home Reference (GHR) contains information on Alpha-1 antitrypsin deficiency. This website is maintained by the National Library of Medicine.

MedlinePlus was designed by the National Library of Medicine to help you research your health questions, and it provides more information about this topic.

The National Heart, Lung, and Blood Institute (NHLBI) has information on this topic. NHLBI is part of the National Institutes of Health and supports research, training, and education for the prevention and treatment of heart, lung, and blood diseases.

The National Human Genome Research Institute’s (NHGRI) website has an information page on this topic. NHGRI is part of the National Institutes of Health and supports research on the structure and function of the human genome and its role in health and disease.

The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.

The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.

Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine.

Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.

PubMed is a searchable database of medical literature and lists journal articles that discuss Alpha-1 antitrypsin deficiency. Click on the link to view a sample search on this topic.

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