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

• Pulmonary Emphysema
• Respiratory Distress Syndrome, Acute

LUNG DISEASE
Alpha-1 Antitrypsin deficiency-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 may develop by the time the person reaches the age of 40 - 50 years. Due to the early onset of emphysema, individuals affected by A1AD are often misdiagnosed as having asthma and experience long diagnostic delays and visits to many different health care providers before the diagnosis is made for the first time.

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

The lower parts of the lungs experience the predominant damage, though a more "classic" X-ray with predominant changes in the upper lung zones may also be seen in a minority of instances.

LIVER DISEASE
Liver disease caused by 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 bleeding from the esophagus or stomach, 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 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.

Chronic degenerative changes in the liver (cirrhosis) eventually develop in up to 30-40% of individuals with severe deficiency of A1AT, perhaps especially in individuals who escape the associated emphysema. Because the pathogenesis of the liver disease (accumulation of unsecreted protein within the liver cells) differs from that of the emphysema (proteolytic damage to the lung support tissues), liver disease may occur separately from the emphysema (though both co-occur in some individuals). 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.

PANNICULITIS
The dermatologic 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 may occur in individuals with various phenotypes, not confined to those associated with severe deficiency of A1AT (e.g., PI*ZZ).
Panniculitis seems to develop in only a few patients with A1AD. The pathogenesis of the disease and why it occurs so rarely is unknown, though the favorable effects of augmenting serum levels of A1AD with infused, purified A1AD protein suggests that panniculitis may be on the basis of unopposed proteolytic activity in the skin.

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.

Deficiency of Alpha-1 Antitrypsin (A1AT) in the blood generally results from the impaired release of A1AT from the liver, where most of it is manufactured. There appears to be an impairment in the release of antiprotease in the liver cells (hepatocytes) of people with Alpha-1 Antitrypsin Deficiency (A1AD) of specific phenotypes (e.g., PI*ZZ, PI*Mmalton); in these instances, this accumulation within the liver cell results from aggregation (polymerization) of A1AT protein within the liver cell, preventing its secretion into the bloodstream. The gene controlling the production of A1AT is located on chromosome 14. About 100 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-1Antitrypsin Deficiency is inherited as an autosomal co-dominant genetic trait, though is sometimes considered to shoe autosomal recessive inheritance. 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 (heterozygote), 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 most cases of Alpha-1 Antitrypsin Deficiency go unrecognized, the disorder is under-diagnosed.

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 less common hereditary form of emphysema, which accounts for ~3% of all instances of emphysema.

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. Official guidelines suggest that all individuals with symptomatic chronic obstructive pulmonary disease (COPD) should be tested for A1AT, as should all first-degree relatives of individuals found to have severe A1AD, individuals with panniculitis, and individuals with unexplained liver disease or bronchiectasis.

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. As noted above, however, underrecognition may result from testing only a minority of at-risk individuals; thus, recommendations for testing suggest that all individuals with symptomatic COPD, along with other groups as noted above, should be tested for A1AT.

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

Treatment
Treatments for emphysema associated with Alpha-1Antitrypsin Deficiency (A1AD) include medications used in managing all patients with emphysema of any cause (such as bronchodilators, steroids, anticholinergics, oxygen therapy, and the administration of antibiotics for the frequent respiratory infections) as well as (in specific subgroups) specific treatment called augmentation therapy. 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.

Specific treatment of A1AD (for individuals with established emphysema) may also involve the use of augmentation therapy, which is the regular, long-term infusion into the veins of deficient individuals of pooled human plasma-derived A1AD. Currently, three drugs for augmentation therapy have received approval by the U.S. Food and Drug Administration - Prolastin, Aralast, and Zemaira. Though definitive studies are needed, the best available evidence suggests that augmentation therapy may help slow the progression of lung damage due to A1AD.

Prolastin is currently produced by talecris Biotherapeutics, Inc. Aralast is produced by Baxter, Inc., and Zemaira is produced by CSL-Behring, Inc. Contact information regarding these drugs is:

Lung volume reduction surgery (LVRS) or the surgical removal of large confluent areas of emphysema (bullae) may be appropriate in highly selected patients, though LVRS may confer less benefit to individuals with emphysema due to A1AD than to individuals with emphysema not due to recognized genetic causes.

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. Liver transplantation may be recommended for individuals with end-stage liver disease.

Genetic counseling may be of benefit for patients and their families. Other family members should be tested for Alpha-1 Antitrypsin deficiency.

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.alphaone.org or call the Foundation at (877) 866-2383.


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.

References
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.