Information on the following diseases can be found in the Related Disorders section of this report:

• Pulmonary Emphysema
• Respiratory Distress Syndrome, Adult

LUNG DISEASE
Alpha-1-Antitrypsin deficiency (A1AD) associated lung disease is characterized by progressive degenerative and destructive changes in the lungs (panacinar emphysema). Emphysema is a chronic, usually slowly progressive illness, which most commonly causes shortness of breath. Other symptoms include chronic cough, phlegm production, and wheezing. Frequent respiratory infections may also be present. 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. Due to the early onset of emphysema, individuals affected by A1AD are often misdiagnosed as having asthma.

Pulmonary Function Tests may reveal reduction in expiratory air flow, hyperinflation, low diffusing capacity, and/or abnormalities on lung scans. An abnormal level of oxygen in the arterial blood (arterial hypoxemia), with or without the retention of carbon dioxide, may also present.

The lower parts of the lungs experience the predominant damage due to greater blood flow and thus most significant impact of a deficiency of the in A1AT protein.

LIVER DISEASE
Liver disease caused by Alpha-1-Antitrypsin deficiency (A1AD) may occur during infancy, childhood, adolescence, or adulthood. Symptoms in infancy include prolonged yellow appearance of the skin (jaundice), mildly elevated liver enzymes, and symptoms of cholestasis (e.g. jaundice, dark urine, pale stools, and itching). Other symptoms may include enlarged liver, bleeding, an abnormal accumulation of fluids within the cavities of the body (ascites), feeding difficulties, and poor growth or failure to thrive. Children and adolescents with this disorder may have symptoms of mildly elevated liver enzymes, severe liver dysfunction, portal hypertension and/or severe liver dysfunction. They may also become easily fatigued, or experience decreased appetite, swelling of the legs or abdomen, and/or enlargement of the liver (hepatomegaly). A1AD associated liver disease symptoms in adults are any or all of the following: chronic active hepatitis, cryptogenic cirrhosis, portal hypertension, and hepatocellular carcinoma.

Other complications that may be seen are an increase of the pressure within blood vessels in the liver (portal hypertension) 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 metablism (urea). A late symptom of this disorder may include an increased susceptibility to infection.

Chronic degenerative changes in the liver (cirrhosis) eventually develop in a small percentage of cases of A1AD. Approximately ten percent of the PiZZ population have serious liver injury.

Examination of liver cells (biopsy) by a pathologist can demonstrate that adults with this hereditary form of emphysema may have liver cell abnormalities similar to those of infants with A1AD who have symptoms of liver involvement. Generally, symptoms of liver involvement do not seem to appear in adult cases where emphysema is the primary symptom although some cases have been reported.

PANNICULITIS
The dermatological manifestation of A1AD is a rare form of skin disease called panniculitis. Panniculitis appears to affect males and females equally, and at any age, and it appears that most individuals with this condition have the PiZZ phenotype, although some have been MZ or of unknown phenotypes.

Panniculitis seems to develop in only a few patients with A1AD. The pathogenesis of the disease and why it occurs so rarely is unknown.

The skin lesions of panniculitis associated with A1AD begin as tender, red and inflamed (erythematous), hardened (indurated), beneath the skin (subcutaneous) nodules, often with an irregular border. The panniculitis is often widely disseminated on the torso or extremities, and is characterized by ulceration in addition to serosanguineous (serum and blood) drainage and accompanying systemic symptoms, including fever.

In a large percentage of cases, direct trauma often precedes the development of the lesions.

Deficiencies of Alpha-1-Antitrypsin (A1AT) in the blood result from the impaired release of A1AT from the liver, where most of it is manufactured. There appears to be an impairment in the storage or release of antiprotease in the liver cells (hepatocytes) of people with Alpha-1- Antitrypsin Deficiency (A1AD). The gene controlling the production of A1AT is located on chromosome 14. About 75 different defects for this gene have been recorded so far. It is not known why only some people with A1AD get symptoms of liver disease while others are primarily affected by lung disease.

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 an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.

Alpha-1-Antitrypsin Deficiency (A1AD) is a disorder that occurs most frequently in Americans of Northern or Central European descent, affecting approximately 100,000 Americans. However, because some cases of Alpha-1-Antitrypsin Deficiency go unrecognized, the disorder is under-diagnosed, making it difficult to determine the true frequency of Alpha-1-Antitrypsin Deficiency in the general population.
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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.

Diagnosis
The diagnosis of Alpha-1-Antitrypsin Deficiency may be confirmed by a variety of specialized tests. Alpha-1-Antitrypsin Deficiency is often misdiagnosed as allergies, asthma or chronic bronchitis. Therefore, it is recommended that individuals with chronic bronchitis, emphysema or asthma be tested for the disorder.

This disorder may be suspected when emphysema occurs in a young person, a nonsmoker, or someone with a family history of emphysema. A1AD should also be suspected in individuals with jaundice, hepatitis, portal hypertension, hepatocellular carcinoma, or someone with a family history of liver disease.

Diagnosis of paniculitis is made by biopsy specimens of the skin lesions and immunologic assay to determine the level of circulating A1AT.

Treatment
Treatments for emphysema associated with Alpha-1-Antitrypsin Deficiency (A1AD) include medications such as bronchodilators, steroids, anticholinergics, oxygen therapy, and the administration of antibiotics for the frequent respiratory infections. Exercise programs and good nutrition 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 non-medical aerosol sprays, etc.

A1AD is also treated with the drug Prolastin, an A1AT replacement therapeutic, which is a purified and treated form of A1AT derived from human plasma and administered by periodic intravenous infusion. Prolastin may help slow the progression of A1AD. Prolastin is manufactured by Bayer Corporation. Recently, Bayer announced that the distribution of Prolastin will be exclusively handled by Bayer Direct, an arm of the manufacturer. Bayer Direct says that all patients, old and new, will have equal access to Prolastin. However patients MUST enroll or register with Bayer Direct. Bayer Direct has established a direct line to handle registration and inquiries. That telephone number is 800-305-7881.

A second enzyme replacement therapy, known as Zemaira, has been approved by the U.S. Food and Drug Administration for the treatment of A1AD. The manufacturer is Aventis Behring. Patients seeking further information should contact:

Kim Cayz
PO Box 61501
1020 First Avenue
King of Prussia, PA 19406, USA
Telephone: (610) 878-4822
Fax: (610) 878-4221
email: Kim.Cayz@aventis.com

Lung volume reduction surgery or the surgical removal of large confluent areas of emphysema (bullae) may be appropriate in highly selected patients.

Lung transplantation, single and double, has been performed successfully on many A1AD patients. This treatment option is performed only on patients with end-stage severe lung disease.

Treatment of liver disease associated with Alpha-1-Antitrypsin Deficiency (A1AD) 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 for 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.

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.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

The Alpha-1 Foundation maintains a patient registry for information regarding research on alpha-1-antitrypsin deficiency. For information or to register, go to www.alpha1.org or call the foundation at (877) 866-2383.

A Phase iI study sponsored by the Alpha-1 Foundation is investigating (2005) the drug 4 phenyl butyrate (4PBA) as a possible treatment for alpha-1 antitrypsin deficiency. This study is being conducted at the University of Florida Health Science Center in Gainesville. For information, contact Dawn Baker, MSN, at (352) 392-8284 or dawn@alphaone.ufl.edu or Pam Schreck, MSN, at (352) 294-0512 or pschreck@ufl.edu.

Researchers are studying the use of gene therapy as a possible treatment for alpha-1-antitrypsin deficiency. More studies are needed to determine the long-term safety and effectiveness of this treatment.

Dr. Edwin Silverman of Harvard Medical School has started a multi-center study looking at the role of genetic modifiers in altering the risk of lung disease in patients with alpha 1-antitrypsin deficiency. Further information is available by calling (tollfree) the research team at (866) 328-9494 or contacting James Keary at the Channing Laboratory at Harvard at rejmk@channing.harvard.edu.

In 2004, Baxter Healthcare Corporation completed a phase III trial of alpha 1-proteinase inhibitor {human} (ARALAST) for the treatment of hereditary emphysema.

The biotechnology company PPL Therapeutics is testing a form of the ATT enzyme made in transgenic sheep that have been genetically altered to make large quantities of ATT in their milk. The product is being tested in individuals with alpha-1-antitrypsion deficiency and cystic fibrosis.

The drug, CTX-100 (formerly ETX-100) received orphan drug status from the FDA in 2002. CTX-100 is a formulation of hyaluronic acid, and researchers believe that it has the potential to treat lung disease associated with alpha-1-antitrypsin deficiency. The drug’s producer, CoTherix, has recently (2005) completed two Phase I trials and plans additional studies in the future on this drug.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 107400; Last Update:12/16/98.

TEXTBOOKS
Beers MH, Berkow R, eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:376.

Scriver CR, et al., eds. The Metabolic and Molecular Basis of Inherited Disease. 7th Ed. New York, NY; McGraw-Hill Companies, Inc; 1995: 4125-58.

Buyce ML, ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:91.

Fishman AP, ed. Pulmonary Diseases and Disorders, 2nd ed. New York, NY: McGraw-Hill Book Company; 1988:2657-58.

JOURNAL ARTICLES
Fischer S, et al. Current status of lung transplantation: patients, indications, techniques and outcome. Med Klin. 2002;97:137-43.

Davies JC, et al. Prospects for gene therapy in lung disease. Curr Opin Pharmacol. 2001;1:272-77.

Coakley RJ, et al. Alpha-1-antitrypsin deficiency: biological answers to clinical questions. Am J Med Sci. 2001;321:33-41.

Campbell EJ. Alpha-1-antitrypsin deficiency: incidence and detection program. Respir Med. 2000;94:S18-21.

Crystal RG, ed. Alpha-1-antitrypsin deficiency; Marcel Dekker, Inc.; 1996. Pp. 3.

Crystal RG. Alpha-1-antitrypsin deficiency: pathogenesis and treatment. Hosp Prac. 1991;26:81-4, 88-9, 93-94.

Birrer P. Alpha-1-antitrypsin deficiency and liver disease. J Inherit Metab Dis. 1991;14:512-25.