sábado, 8 de octubre de 2016

Alpha-1 antitrypsin deficiency | Genetic and Rare Diseases Information Center(GARD) – an NCATS Program

Alpha-1 antitrypsin deficiency | Genetic and Rare Diseases Information Center(GARD) – an NCATS Program

National Center for Advancing and Translational SciencesGenetic and Rare Diseases Information Center, a program of the National Center for Advancing and Translational Sciences

Alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin deficiency (AATD) is a disorder that causes a deficiency or absence of the alpha-1 antitrypsin (AAT) protein in the blood. AAT is made in the liver and sent through the bloodstream to the lungs, to protect the lungs from damage. Having low levels of ATT (or no ATT) can allow the lungs to become damaged, making breathing hard. Age of onset and severity of AATD can vary based on how much ATT an affected person is missing. In adults, symptoms may include shortness of breath; reduced ability to exercise; wheezing; respiratory infections; fatigue; vision problems; and weight loss. Some people have chronic obstructive pulmonary disease (COPD) or asthma. Liver disease (cirrhosis) may occur in affected children or adults. Rarely, AATD can cause a skin condition called panniculitis.[1] AATD is caused by mutations in theSERPINA1 gene and is inherited in a codominant manner.[2] Treatment is based on each person's symptoms and may include bronchodilators; antibiotics for upper respiratory tract infections; intravenous therapy of AAT; and/or lung transplantation in severe cases.[1][3]
Last updated: 4/6/2016

The Human Phenotype Ontology (HPO) provides the following list of features that have been reported in people with this condition. Much of the information in the HPO comes from Orphanet, a European rare disease database. If available, the list includes a rough estimate of how common a feature is (its frequency). Frequencies are based on a specific study and may not be representative of all studies. You can use theMedlinePlus Medical Dictionary for definitions of the terms below.
Signs and SymptomsApproximate number of patients (when available)Help
Hepatic failure90%
Nephrotic syndrome7.5%
Autosomal recessive inheritance-
Chronic obstructive pulmonary disease-
Elevated hepatic transaminases-
Hepatocellular carcinoma-

Last updated: 10/1/2016

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.

The severity of AATD may also be worsened by environmental factors such as exposure to tobacco smoke, dust, and chemicals.[2]
Last updated: 4/7/2016

Alpha-1 antitrypsin deficiency (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]
Last updated: 4/7/2016

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]
Last updated: 4/8/2016

Management Guidelines

  • 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.  

    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 Talecris Biotherapeutics 
      FDA-approved indication: For chronic replacement therapy of individuals having congenital deficiency of alpha1- proteinase inhibitor with clinically demonstrable panacinar emphysema. 
      National Library of Medicine Drug Information Portal

    Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

    Clinical Research Resources

    • ClinicalTrials.gov lists trials that are studying or have studied Alpha-1 antitrypsin deficiency. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

      Nonprofit support and advocacy groups bring together patients, families, medical professionals, and researchers. These groups often raise awareness, provide support, and develop patient-centered information. Many are the driving force behind research for better treatments and possible cures. They can direct people to research, resources, and services. Many groups also have experts who serve as medical advisors. Visit their 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

          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. Contact 800-785-3177 to ask a genetic counselor questions about alpha 1 antitrypsin deficiency.

            Genetics Resources

              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.

                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.

                    Selected Full-Text Journal Articles

                      Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know. Submit a new question
                      • I have been recently diagnosed with the alpha-1 antitrypsin deficiency gene along with my brother. He found out he had it and told the family we should get checked because it's inherited. I'm level 25 and he is level 30. My question is what is the treatment process for the disease? My brother and I are almost 60 but our kids are still young. What would the process be for them? See answer
                      • My birth mother's maternal half-sister died from this disease. What are the chances of me or one of my six children having this genetic disorder? See answer
                      • I think I may have alpha-1-antitrypsin deficiency. How is it diagnosed? Who should I talk to? See answer
                      • What are the chances of having alpha 1-antitrypsin deficiency and panniculitis? See answer

                      1. Learning About Alpha-1 Antitrypsin Deficiency (AATD). NHGRI. January 4, 2012;https://www.genome.gov/19518992.
                      2. Alpha-1 antitrypsin deficiency. Genetics Home Reference. January 2013;http://www.ghr.nlm.nih.gov/condition/alpha-1-antitrypsin-deficiency.
                      3. James K Stoller, Felicitas L Lacbawan, and Loutfi S Aboussouan. Alpha-1 Antitrypsin Deficiency.GeneReviews. May 1, 2014; http://www.ncbi.nlm.nih.gov/books/NBK1519/.
                      4. What Is Alpha-1 Antitrypsin Deficiency?. NHLBI. October, 2011; http://www.nhlbi.nih.gov/health/health-topics/topics/aat.

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