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$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
     [phone]

     Alpha-1 National Association
     1829 Portland Ave.
     Minneapolis, MN  55404
     [phone]

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
     [phone]

     NIH/National Heart, Lung and Blood Institute (NHLBI)
     9000 Rockville Pike
     Bethesda, MD  20892
     [phone]

     American Lung Association
     1740 Broadway
     New York, NY 10019
     [phone]

     American Liver Foundation
     998 Pompton Ave.
     Cedar Grove, NJ  07009
     [phone]

     Children's Liver Foundation
     14245 Ventura Blvd.
     Sherman Oaks, CA  91423
     [phone]

For Genetic Information and Genetic Counseling Referrals:

     March of Dimes Birth Defects Foundation
     1275 Mamaroneck Ave.
     White Plains, NY  10605
     [phone]

     Alliance of Genetic Support Groups
     25 Wisconsin Circle, Suite 440
     Chevy Chase, MD  20815
     (800) 336-GENE
     [phone]

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.