Rare Ophthalmology News

Disease Profile

Alpha-1 antitrypsin deficiency

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
1-5 / 10 000

33,100 - 165,500

US Estimated

1-5 / 10 000

51,350 - 256,750

Europe Estimated

Age of onset

All ages

ageofonset-all.svg

ICD-10

E88.0

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

no.svg

Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

rnn-autosomalrecessive.svg

X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

no.svg

X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

no.svg

Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

no.svg

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

no.svg

Not applicable

no.svg

Other names (AKA)

AAT deficiency; A1AT deficiency; AATD;

Categories

Congenital and Genetic Diseases; Digestive Diseases; Kidney and Urinary Diseases;

Summary

Alpha-1 antitrypsin deficiency (AATD) is an inherited disease that causes an increased risk of having chronic obstructive pulmonary disease (COPD), liver disease, skin problems (panniculitis), and inflammation of the blood vessels (vasculitis).[1][2][3] Lung (pulmonary) problems almost always occur in adults, whereas liver and skin problems may occur in adults and children.[2] The age symptoms begin and severity of symptoms can vary depending on how much working alpha-1 antitrypsin protein (AAT) a person has. Symptoms may include shortness of breath and wheezing, repeated infections of the lungs and liver, yellow skin, feeling overly tired (fatigue), rapid heartbeat when standing, vision problems, and weight loss. However, some people with AATD do not have any problems.[1][2][3]

AATD is caused by changes (pathogenic variants, also called mutations) in the SERPINA1 gene and it is inherited in a codominant manner.[4] The genetic changes cause too little or no working alpha-1 antitrypsin protein (AAT) to be made. AAT is made in the liver cells and sent through the bloodstream to the lungs where it helps protect the lungs from damage. Having low levels of AAT (or no AAT) may allow the lungs to become damaged. A build-up of abnormal AAT can cause liver damage.[1][2][4] Diagnosis may be suspected by finding low levels of AAT in the blood and confirmed by genetic testing.[1][2] Treatment may include infusions of AAT. Other treatment depends on the type and severity of the person's medical problems, but may include bronchodilators to open airways, antibiotics for upper respiratory tract infections, and in severe cases, lung transplantation or liver transplantation.[2][3][5]

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.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Emphysema
0002097
Hepatic failure
Liver failure
0001399
30%-79% of people have these symptoms
Hepatitis
Liver inflammation
0012115
Hepatomegaly
Enlarged liver
0002240
Jaundice
Yellow skin
Yellowing of the skin

[ more ]

0000952
5%-29% of people have these symptoms
Cirrhosis
Scar tissue replaces healthy tissue in the liver
0001394
Nephrotic syndrome
0000100
1%-4% of people have these symptoms
Chronic bronchitis
0004469
Dyspnea
Trouble breathing
0002094
Wheezing
0030828
Percent of people who have these symptoms is not available through HPO
Autosomal recessive inheritance
0000007
Chronic pulmonary obstruction
0006510
Elevated hepatic transaminase
High liver enzymes
0002910
Hepatocellular carcinoma
0001402
Panacinar emphysema
0032967

Cause

Alpha-1 antitrypsin deficiency (AATD) is caused by changes (pathogenic variants, also known as mutations) in the SERPINA1 gene. This gene gives the body instructions to make a protein called alpha-1 antitrypsin (AAT). One of the jobs of AAT is to protect the body from another protein called neutrophil elastase. Neutrophil elastase is an enzyme that helps the body fight infections, but it can also attack healthy tissues (especially the lungs), if not controlled by AAT.[2][4]

Genetic changes that cause AAT may mean that the body's liver cells make too little or no AAT, or make a form (variant) of AAT that does not work well (abnormal AAT). This allows neutrophil elastase to destroy lung tissue, causing lung disease.[1][4] 

In addition, abnormal AAT can build up in the liver and cause damage to the liver, especially in people who have two copies of the specific genetic variant called allele Z (sometimes written as PI*ZZ). Liver problems do not occur in people who do not make any detectable AAT, for example when a person has two null alleles of the SERPINA1 gene.[1][2]

The severity of AATD may also be worsened by environmental factors such as exposure to tobacco smoke, dust, and chemicals.[2][4]

Diagnosis

Alpha-1 antitrypsin deficiency (AATD) may first be suspected in people who have symptoms of liver disease at any age, or who have symptoms of lung disease (such as emphysema), especially when there is no obvious cause or it is diagnosed at a younger age.[2]

Confirming the diagnosis involves a blood test showing a low level the alpha-1 antitrypsin protein (AAT) in the blood, and either:[2]

  • Detecting an AAT protein variant that does not work properly (functionally deficient) using a special test called isoelectric focusing.

or

  • Finding a disease causing change (pathogenic variant, also called mutation) in both copies of the SERPINA1 gene by genetic testing. (This confirms the diagnosis when the above-mentioned tests are not performed or their results are not in agreement.)

Specialists involved in the diagnosis may include primary care doctors, lung specialists (pulmonologists), and/or liver specialists (hepatologists ).[6]

Treatment

In general, the treatment of medical problems associated with alpha-1 antitrypsin deficiency (AATD) includes the standard medical therapies and supportive care for the specific medical problem. However, there is one special therapy available to some people with AATD who have lung problems called augmentation therapy (sometimes called replacement therapy).[2][3][5] 

Augmentation therapy aims to increase the blood level of alpha-1 antitrypsin protein (AAT) by adding purified, human AAT directly into the person's blood through intravenous (IV) infusion. The goal is to prevent the progression of lung disease. Skin problems usually get better as well. Augmentation therapy does not affect liver disease associated with AATD.[2][3][5]

Augmentation therapy is indicated only when people with AATD:[2][5]

  • 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 get the infusions weekly 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.

Other treatments depend on symptoms but may include:[2][3][5]

  • Antibiotics to treat infections.
  • Bronchodilators and inhaled steroids can help open the airways and make breathing easier.
  • Exercise program.
  • Oxygen.
  • 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.

Routine recommendations to avoid medical complications include:[2][3][5]

  • Vaccination against hepatitis A and B.
  • Preventive vaccines against influenza and pneumococcal vaccines.
  • Avoid using tobacco.
  • Avoid or minimize drinking alcohol (for those at risk for liver disease).
  • Avoid other environmental risk factors such as chemical exposures.
  • Liver function tests periodically for people with two copies of the Z allele (PI*ZZ).
  • Lung function test every six to 12 months people with severe AATD.
  • Liver ultrasound, in cases of liver disease, every 6 to 12 months to monitor for fibrotic changes (cirrhosis) and liver cancer (hepatocellular carcinoma).

Management Guidelines

  • 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.

    FDA-Approved Treatments

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

    • 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 alpha1proteinase inhibitor with clinically demonstrable panacinar emphysema.
      National Library of Medicine Drug Information Portal

    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.

    Organizations Supporting this Disease

      Organizations Providing General Support

        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

        • MedlinePlus was designed by the National Library of Medicine to help you research your health questions, and it provides more information about this topic.
        • Genetics Home Reference (GHR) contains information on Alpha-1 antitrypsin deficiency. This website is maintained by the National Library of Medicine.
        • 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

          • 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.
          • 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.

            Selected Full-Text Journal Articles

              References

              1. Stoller JK. Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency. UpToDate. May 25, 2018; https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-natural-history-of-alpha-1-antitrypsin-deficiency.
              2. Stoller JK, Lacbawan FL, Aboussouan LS. Alpha-1 Antitrypsin Deficiency. GeneReviews. January 19, 2017; https://www.ncbi.nlm.nih.gov/books/NBK1519/.
              3. Stoller JA. Extrapulmonary manifestations of alpha-1 antitrypsin deficiency. UpToDate. May 23, 2018; https://www.uptodate.com/contents/extrapulmonary-manifestations-of-alpha-1-antitrypsin-deficiency.
              4. Alpha-1 antitrypsin deficiency. Genetics Home Reference. January 2013; https://ghr.nlm.nih.gov/condition/alpha-1-antitrypsin-deficiency.
              5. Stoller JK. Treatment of alpha-1 antitrypsin deficiency. UpToDate. April 20, 2018; https://www.uptodate.com/contents/treatment-of-alpha-1-antitrypsin-deficiency.
              6. Alpha-1 Antitrypsin Deficiency. National Heart, Lung, and Blood Institute (NHLBI). October 2011; https://www.nhlbi.nih.gov/health-topics/alpha-1-antitrypsin-deficiency.

              Rare Ophthalmology News