$Unique_ID{BRK03444} $Pretitle{} $Title{Alpha-1-Antitrypsin Deficiency} $Subject{Alpha-1-Antitrypsin Deficiency Homozygous Alpha-1-Antitrypsin Deficiency Cholestasis, Neonatal AAT Deficiency A1AT Deficiency Familial Emphysema Familial Chronic Obstructive Lung Disease Pi Phenotype ZZ, Sz, Z- Hereditary Emphysema Serum Protease Inhibitor Deficiency Antitrypsin Deficiency Protease Inhibitor Deficiency PI AAT Pulmonary Emphysema Respiratory Distress Syndrome, Adult} $Volume{} $Log{} Copyright (C) 1985, 1988, 1990, 1991, 1993 National Organization for Rare Disorders, Inc. 53: Alpha-1-Antitrypsin Deficiency ** IMPORTANT ** It is possible that the main title of the article (Alpha-1-Antitrypsin Deficiency) is not the name you expected. Please check the SYNONYMS listing to find the alternate name and disorder subdivisions covered by this article. Synonyms Homozygous Alpha-1-Antitrypsin Deficiency Cholestasis, Neonatal AAT Deficiency A1AT Deficiency Familial Emphysema Familial Chronic Obstructive Lung Disease Pi Phenotype ZZ, Sz, Z- and -- Hereditary Emphysema Serum Protease Inhibitor Deficiency Antitrypsin Deficiency Protease Inhibitor Deficiency PI AAT Information on the following diseases can be found in the Related Disorders section of this report: Pulmonary Emphysema Respiratory Distress Syndrome, Adult General Discussion ** REMINDER ** The Information contained in the Rare Disease Database is provided for educational purposes only. It should not be used for diagnostic or treatment purposes. If you wish to obtain more information about this disorder, please contact your personal physician and/or the agencies listed in the "Resources" section of this report. Alpha-1-Antitrypsin Deficiency is a rare hereditary metabolic disease characterized by low levels of the enzyme Alpha-1-Antitrypsin. A deficiency of this enzyme allows substances which break down protein (proteolytic enzymes) to attack various tissues of the body. This results in destructive changes in the lungs (emphysema), and may also affect the liver and joints. Alpha-1-Antitrypsin is ordinarily released by specialized, granular white blood cells (neutrophils) in response to infection or inflammation. A deficiency of Anti-1-Antitrypsin results in uncontrolled rapid breakdown of proteins (protease activity), especially in the foundation membranes (basilar) of the lung. Symptoms Alpha-1-Antitrypsin deficiency is characterized by progressive degenerative and destructive changes in the lungs (panacinar emphysema). The initial symptoms may be seen as early as the age of 20 years in people who have inherited one of the two identical genes for this disorder from each parent (homozygous). The more serious changes that occur in the lungs and other organs of the body usually develop by the time the person reaches the age of 30 or 40 years. The earliest symptom of Alpha-1-Antitrypsin deficiency is a progressive shortness of breath. A chronic cough or frequent respiratory infections may also be present. The most severe symptoms of this disorder usually develop by the age of 55 to 60 years. Other early symptoms of Alpha-1-Antitrypsin deficiency, frequently seen in people who are Anti-1-Antitrypsin deficient but without symptoms, may include over-inflation and loss of elastic recoil in the lungs. Medical testing of the lungs may reveal low forced expiratory volume, low diffusing capacity, and/or abnormalities on lung scans. An abnormal deficiency of oxygen in the arterial blood (arterial hypoxemia), with or without the retention of carbon dioxide, may also present. Defects in the rate at which oxygen is exchanged by the lungs are most often seen in the areas at the base of the lungs, particularly early in the course of this disorder. There may be low Alpha-1-Antitrypsin (AAT) levels in the blood. Symptoms of liver involvement caused by Alpha-1-Antitrypsin deficiency may occur during infancy, childhood or adolescence. Infants may have a yellow appearance to the skin (jaundice), an abnormal accumulation of fluids within the cavities of the body (ascites), and/or poor feeding habits. Children and adolescents with this disorder may experience easy fatigue, decreased appetite, swelling of the legs or abdomen, and/or enlargement of the liver (hepatomegaly). About 25 percent of infants with symptoms of liver involvement experience no further complications, and involvement of the liver seems to end after infancy. Chronic degenerative changes in the liver (cirrhosis) eventually develop in a small percentage of cases of Alpha-1-Antitrypsin Deficiency. There may be an increase of the pressure within blood vessels in the liver that may result in nosebleeds, easy bruising, fluid accumulation in the chest, abnormally enlarged vessels within the stomach or esophagus, and/or occasional internal bleeding. Laboratory tests of liver function generally have abnormal results. Later in the course of the cirrhosis, drowsiness may occur after protein-rich meals because the liver is unable to properly dispose of the waste products of protein metabolism (urea). A late symptom of this disorder may include an increased susceptibility to infection. Examination of liver cells by a pathologist can demonstrate that adults with this hereditary form of emphysema may have liver cell abnormalities similar to those of infants with Alpha-1-Antitrypsin Deficiency who have symptoms of liver involvement. Generally no symptoms of liver involvement seem to appear in adult cases where emphysema is the primary symptom. Other less common symptoms of Alpha-1-Antitrypsin deficiency may include degenerative joint disease, abnormalities of blood clotting, and kidney disease. Causes Alpha-1-Antitrypsin Deficiency is inherited as an autosomal recessive genetic trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If one receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will show no symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is twenty-five percent. Fifty percent of their children will be carriers, but healthy as described above. Twenty-five percent of their children will receive both normal genes, one from each parent, and will be genetically normal. The genes for Alpha-1-Antitrypsin Deficiency are located on chromosome 14. About 75 different genetic defects for this gene have been recorded so far. Deficiencies of Alpha-1-Antitrypsin in the blood result from the impaired release of Alpha-1-Antitrypsin from the liver, where it is manufactured. The normal levels of Alpha-1-Antitrypsin rise quickly in response to physical stress but they may be unable to release enough alpha-1-antitrypsin to meet their needs. There appears to be an impairment in the storage or release of antiprotease in the liver cells (hepatocyte) of people with Alpha-1- Antitrypsin Deficiency. It is not known why only some people with Alpha-1- Antitrypsin Deficiency get symptoms of liver disease, and others are primarily affected by lung disease. Affected Population Alpha-1-Antitrypsin Deficiency is a rare disorder that occurs most frequently in Americans of Northern or Central European descent. This disorder may be suspected when emphysema occurs in a young person, a nonsmoker, or someone with a family history of emphysema. Related Disorders Symptoms of the following disorders can be similar to those of Alpha-1- Antitrypsin Deficiency. Comparisons may be useful for a differential diagnosis: Pulmonary Emphysema is a common, chronic obstructive disease of the lungs characterized by the enlargement of the air spaces in the lungs and destructive changes to the walls of the lungs. The lungs lose their elasticity; there is a progressive decrease in the ability of the lungs to exchange oxygen that must be carried to the tissues of the body by the blood. Symptoms of emphysema typically include a progressive shortness of breath, a chronic cough that frequently produces sputum, wheezing, weakness, and/or frequent respiratory infections. The exact cause of Pulmonary Emphysema is unknown, although it is often associated with cigarette smoking, allergy, asthma, and/or chronic lung disease. Alpha-1-Antitrypsin Deficiency is a rare hereditary form of emphysema. Adult Respiratory Distress Syndrome is a serious disorder of the lungs that may be caused by a variety of lung injuries or acute illnesses that damage the small vessels of the lungs. The major symptoms of this disorder include chest pain around the ribs, difficulty breathing, an abnormally high rate of breathing, hyperventilation and/or low levels of oxygen in the blood. Complications of Adult Respiratory Distress Syndrome may include blood clots in the lungs, abnormal kidney function, abnormal heart rhythms and/or anemia. (For more information, choose "Adult Respiratory Distress Syndrome" as your search term in the Rare Disease Database.) Other common disorders of protease-antiprotease imbalance include Chronic Bronchitis, pneumonia, and pancreatitis. Therapies: Standard Treatments for emphysema associated with Alpha-1-Antitrypsin Deficiency include oxygen therapy and the administration of antibiotics for the frequent respiratory infections. Exercise programs may help increase overall quality of daily living. It is very important that people with emphysema avoid smoking, employment that exposes the patient to lung irritants, and the use of aerosol sprays, etc. Treatment of liver disease associated with Alpha-1-Antitrypsin Deficiency is aimed at relieving symptoms. Phenobarbital or cholestyramine are often prescribed to relieve itching and control jaundice. Diuretics (water pills) and potassium are used to maintain electrolyte balance and to prevent the retention of water. Proper nutrition is essential for people with this disorder. Surgery may become necessary in some people with liver disease associated with Alpha-1-Antitrypsin Deficiency. Shunts may be inserted to lower the pressure within the blood vessels in the liver. Liver transplantations have been attempted, but with limited success on some patients with late stage liver disease due to Alpha-1-Antitrypsin Deficiency. Alpha-1-Antitrypsin Deficiency is also treated with the orphan drug, alpha-1-proteinase inhibitor (Prolastin), which is manufactured by Cutter Biological, Division of Miles, Inc. This drug inhibits the action of alpha- 1-proteinase and thus replaces the deficient alpha-1-antitrypsin. Prolastin can arrest the symptoms of Alpha-1-Antitrypsin Deficiency and prevent the symptoms from getting worse. Genetic counseling may be of benefit for patients and their families. Other family members should be tested for Alpha-1-Antitrypsin deficiency because early treatment with Prolastin can arrest progression of lung disease. Therapies: Investigational Experimental drugs being investigated to treat Alpha-1-Antitrypsin Deficiency include synthetic neutrophil elastase inhibitors, Danazol, certain acylating agents, sulfonyl fluorides, short chain fatty acids, and chloromethyl ketone peptides. Researchers are also trying to develop an aerosolized synthetic form of Prolastin that would deliver the drug directly to the lungs. An Alpha-1-Antitrypsin registry has been established by the National Heart, Lung and Blood Institute (NHLBI) at 22 clinical centers throughout the country. Patients who participate in the registry are seen every six months for five years. Patients who wish to learn more about participation in the registry will find the address listed in the "Resources" section of this report. Lung transplants, for people with Alpha-1-Antitrypsin Deficiency, have been performed at the Minnesota Heart and Lung Institute in Minneapolis, the University of California at San Diego, and Barnes Hospital in St. Louis. Although several attempts have been successful, it is still too early to determine whether lung transplants will be as effective as liver transplants. Another new treatment being tested is the administration of Secretory Leukocyte Protease Inhibitor (SLPI). This drug is being tested in collaboration with the National Heart, Lung & Blood Institute (NHLBI) and the manufacturer, Synergen, Inc. of Colorado. Information on these trials can be obtained from the National Heart, Lung & Blood Institute, listed in the Resources section of this report. Scientists are investigating the possibility of gene therapy for the treatment of Alpha-1-Antitrypsin Deficiency. Current research on the transfer of the Cystic Fibrosis gene into the lungs of Cystic Fibrosis patients has raised the question of whether the same can be done for Alpha-1- Antitrypsin Deficiency patients. Transfer of the Alpha-1-Antitrypsin gene into the liver of patients with AAT deficiency is also possible in the future. Experiments on animals are underway to determine which type of gene therapy would be most beneficial for humans with Alpha-1-Antitrypsin Deficiency. This disease entry is based upon medical information available through February 1993. Since NORD's resources are limited, it is not possible to keep every entry in the Rare Disease Database completely current and accurate. Please check with the agencies listed in the Resources section for the most current information about this disorder. Resources For more information on Alpha-1-Antitrypsin Deficiency contact: National Organization for Rare Disorders (NORD) P.O. Box 8923 New Fairfield, CT 06812-1783 (203) 746-6518 Alpha-1 National Association 1829 Portland Ave. Minneapolis, MN 55404 (612) 871-7332 To locate AAT Registry Clinics: Alpha-1-Antitrypsin Deficiency Registry The Cleveland Clinic Foundation David P. Meeker, M.D. Dept. of Pulmonary Diseases 9500 Euclid Ave. Cleveland, OH 44195 (216) 444-6505 NIH/National Heart, Lung and Blood Institute (NHLBI) 9000 Rockville Pike Bethesda, MD 20892 (301) 496-4236 American Lung Association 1740 Broadway New York, NY 10019 (212) 315-8700 American Liver Foundation 998 Pompton Ave. Cedar Grove, NJ 07009 (201) 857-2626 Children's Liver Foundation 14245 Ventura Blvd. Sherman Oaks, CA 91423 (818) 906-3021 For Genetic Information and Genetic Counseling Referrals: March of Dimes Birth Defects Foundation 1275 Mamaroneck Ave. White Plains, NY 10605 (914) 428-7100 Alliance of Genetic Support Groups 25 Wisconsin Circle, Suite 440 Chevy Chase, MD 20815 (800) 336-GENE (301) 652-5553 References MENDELIAN INHERITANCE IN MAN, 10th Ed.: Victor A. McKusick, Editor: Johns Hopkins University Press, 1992. Pp. 92-94. PULMONARY DISEASES AND DISORDERS, Alfred P. Fishman, 2nd. ed. McGraw- Hill Book Company, 1988, Vol. II. Pp. 1204-1269, 1544. THE MERCK MANUAL, 16th Ed.: Robert Berkow Ed.; Merck Research Laboratories, 1992. P. 911. THE METABOLIC BASIS OF INHERITED DISEASE, 6th Ed.: Charles R. Scriver, et al., Editors; McGraw Hill, 1989. Pp. 2417-2428. BIRTH DEFECTS ENCYCLOPEDIA, Mary Louise Buyse, M.D., Editor-In-Chief; Blackwell Scientific Publications, 1990. P. 91. ALPHA-1-ANTITRYPSIN DEFICIENCY: PATHOGENESIS AND TREATMENT. R.G. Crystal, Hosp Prac (Feb 15, 1991; 26(2)). Pp. 81-4, 88-9, 93-4. ALPHA-1-ANTITRYPSIN DEFICIENCY AND LIVER DISEASE. P. Birrer, J Inherit Metab Dis (1991; 14(4)). Pp. 512-525.