Alpha-1 Antitrypsin Deficiency

Alpha-1 Antitrypsin Deficiency

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Alpha-1 Antitrypsin Deficiency is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • A1AD
  • AATD
  • genetic emphysema

Disorder Subdivisions

  • None

General Discussion

Alpha-1 antitrypsin deficiency (A1AD) is a hereditary disorder characterized by low levels of a protein called alpha-1 antitrypsin (A1AT) which is found in the blood. This deficiency may predispose an individual to several illnesses and most commonly manifests as chronic obstructive pulmonary disease (including bronchiectasis) and liver disease (especially cirrhosis and hepatoma), or more rarely, as a skin condition called panniculitis. A1AD is also more frequent among individuals with Wegener's granulomatosis. A deficiency of A1AT allows substances that break down proteins (so-called proteolytic enzymes) to attack various tissues of the body. The attack results in destructive changes in the lungs (emphysema) and may also affect the liver and skin. Alpha-1 antitrypsin is ordinarily released by specialized, granules within a type of white blood cells (called neutrophils or polymorphonuclear leukocytes) in response to infection or inflammation. Deficiency of alpha-1 antitrypsin results in unbalanced (i.e., relatively unopposed) rapid breakdown of proteins (protease activity), especially in the supporting elastic structures of the lungs. Over years, this destruction leads to progressive emphysema and is accelerated by smoking, some occupational exposures, and likely by other genetic modifiers of this risk which remain incompletely understood.

Symptoms

LUNG DISEASE

Alpha-1 antitrypsin deficiency-associated lung disease is characterized by progressive degenerative and destructive changes in the lungs (emphysema, commonly of the panacinar type). Emphysema is a chronic, usually slowly progressive illness, which most commonly causes shortness of breath. Other symptoms may include chronic cough, phlegm production, and wheezing. Frequent respiratory infections may also occur. 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 (but may also occur only later in life). Individuals affected by A1AD often experience long diagnostic delays and visits too 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 a CT scan of the chest may show loss of lung tissue that may not be apparent on breathing test results. An abnormal level of oxygen in the arterial blood (arterial hypoxemia), with or without the retention of carbon dioxide, may also occur, especially in more advanced lung disease.



Most commonly, changes are evident in the lower lung zones of plain chest X-rays or CT scans (about 2/3 of cases), though more classic changes of emphysema that affect predominantly the upper lung zones also occur in a minority of individuals.



LIVER DISEASE

Liver disease caused by A1AD may occur during infancy, childhood, adolescence, or only newly during 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 findings in adults are any or all of the following: chronic active hepatitis, cirrhosis, portal hypertension, and hepatocellular carcinoma.



Other complications that may occur are an increase of the pressure within blood vessels in the liver (portal hypertension) that may cause bleeding from the esophagus or stomach, easy bruising, fluid accumulation in the chest, abnormally enlarged vessels within the stomach or esophagus, and/or a generally increased bleeding risk. Laboratory tests of liver function may have abnormal results and the assessment of patients for and with liver disease increasingly depend on imaging studies (i.e., liver ultrasound, etc.).



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



PANNICULITIS

The dermatologic manifestation of A1AD is a rare form of skin disease called panniculitis. Panniculitis appears to affect males and females equally, occurs at any age, and may occur in individuals with various phenotypes, not confined to those associated with severe deficiency of A1AT.



Panniculitis seems to develop in only a few patients with A1AD (approximately 1 per thousand individuals with the most common form of severe deficiency, so-called PI*ZZ). The pathogenesis of panniculitis and why it occurs so rarely is unknown, though the observed 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 nodules that are tender, red and inflamed (erythematous), hardened (indurated), and occur beneath the skin (subcutaneous), often with an irregular border. The panniculitis often widely affects the torso or extremities, and is characterized by ulceration in addition to serosanguinous (serum and blood) drainage and accompanying systemic symptoms, including fever.



In some patients, direct trauma often precedes the development of the lesions.

Causes

A1AT is caused by mutations in the SERPINA1 gene that is responsible for production of the alpha-1 antitrypsin protein. This protein is produced in the liver and released in the blood and functions to protect the body from the neutrophil elastase enzyme. A1AT also appears to have anti-inflammatory effects independent of its anti-neutrophil elastase activity. Mutations in the SERPINA1 gene result in production of an abnormal protein that gets trapped in the liver, resulting in low serum levels of A1AT that can predispose to lung breakdown by neutrophil elastase and other proteolytic enzymes. In addition, abnormal A1AT protein can accumulate in the liver and cause damage. Over 120 different mutations in the SERPINA1 gene have been identified, with the most common termed S and Z, whereas the normal version (allele) of the gene is termed M. The S allele produces moderately low levels of protein and the Z allele produces very little protein. Other rare variants, called null, are associated with the complete absence of A1AT in the bloodstream, because no protein is synthesized.



A1AT is inherited as an autosomal co-dominant genetic condition. Co-dominant genetic disorders occur when each inherited allele expresses some effect (like a lowered serum level of A1AT).In general, in a co-dominant condition, when the individual inherits two copies of an abnormal deficient gene for the same trait, one from each parent, the risk of disease is higher than when only one abnormal allele is inherited. People who have two copies of the Z allele (ZZ) have severe deficiency of A1AT and are at high risk of developing emphysema. The risk for two carrier parents to both pass the defective gene and have an affected (ZZ) child is 25% with each pregnancy, and in this circumstance, the risk to have a child who is a carrier like the parents is 50% with each pregnancy. Finally, the chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. In autosomal conditions, the inheritance risk is the same for males and females because the abnormal gene does not reside on the sex chromosomes (X or Y). In A1AT, the SERPIN1A gene resides on the long arm of the 14th chromosome.



If an individual receives one normal allele and one Z allele (MZ), the clinical risk of developing lung disease is considered to be small, though there may be a subset of these so-called heterozygous patients who are at higher risk. If an individual receives one S allele and one Z allele (SZ), they are considered to be at increased risk to develop chronic obstructive pulmonary disease if they smoke.

Affected Populations

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.

Standard Therapies

Diagnosis

The diagnosis of A1AD is based on a low concentration of A1AT blood plasma in combination with a high-risk phenotype (demonstrated by isoelectric focusing) or genotype (by specific allele analysis [especially for the Z and S alleles]).



Because A1AD often goes unrecognized, official guideline documents recommend that all individuals with fixed airflow obstruction on spirometry testing should be tested for the disorder. Also, all first-degree relatives of individuals found to have severe A1AD, individuals with panniculitis, and individuals with unexplained liver disease or bronchiectasis should be tested.



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, under-recognition may result from testing only a minority of at-risk individuals; thus, as noted above, recommendations for testing suggest that all adults with symptomatic COPD, along with other groups cited above, should be tested for A1AD.



Once clinical suspicion is aroused, the diagnosis of panniculitis 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 A1AD include standard medications used in managing patients with emphysema of all causes (such as inhaled bronchodilators, inhaled steroids, anticholinergics, oxygen therapy, and the administration of antibiotics for the frequent respiratory infections) as well as (in specific subgroups) specific A1AT treatment called augmentation therapy. Exercise programs (pulmonary rehabilitation) 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. Preventing infection as possible with yearly influenza and periodic pneumococcal vaccinations is also recommended.



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 purified, pooled human plasma-derived A1AD. Currently, six drugs for augmentation therapy have received approval by the U.S. Food and Drug Administration: Prolastin, Prolastin-C, Aralast, Aralast NP, Zemaira, and Glassia. Though definitive studies are needed, the best available evidence suggests that augmentation therapy may help slow the progression of lung damage due to A1AD.



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.



No specific therapy is available for the liver disease associated with A1AD and management is directed at controlling symptoms. Special procedures may become necessary for some people with liver disease associated with A1AD. For example, shunts may be inserted to lower the pressure within the blood vessels in the liver and dilated veins in the food tube (esophagus) may be clipped or banded to lower the risk of bleeding. Liver transplantation may be recommended for individuals with end-stage liver disease.



Genetic counseling is recommended for patients and their families.

Investigational Therapies

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. Promising prospects include gene therapy (by intramuscular injection of a virus carrying the normal human A1AT gene), administration of augmentation therapy by inhalation, and the synthesis of normal A1AT in human or yeast cells for subsequent use in augmentation therapy. Also, studies examining differing doses of intravenous augmentation therapy are underway at this writing.



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



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



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.



Contact for additional information about alpha-1 antitrypsin deficiency:



James K. Stoller, M.D., M.S.

Jean Wall Bennett Professor of Medicine

Cleveland Clinic

9500 Euclid Ave.

Cleveland, OH 44195

(216) 444-1960

stollej@ccf.org

References

TEXTBOOKS

Kohnlein T, Welte T, (eds). Alpha-1 antitrypsin Deficiency: Clinical Aspects and Management. 2nd edition. Bremen: UNI-MED; 2010



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



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

Gadek JE, Crystal RG. Alpha 1-antitrypsin deficiency. In: Scriver CR, et al., eds. The Metabolic and Molecular Basis of Inherited Disease. 7th Ed. New York, NY; McGraw-Hill Companies, Inc; 1995



JOURNAL ARTICLES

Aboussouan LS, Stoller JK. Myths and misconceptions about alpha-1 antitrypsin deficiency. Arch Intern Med 2009; 169: 546 - 550.



Aboussouan LS, Stoller JK. Detection of alpha-1 antitrypsin deficiency: A review. Respir Med 2009;103:335-341.



Modrykamien A, Stoller JK. Alpha-1 antitrypsin (AAT) deficiency - what are the treatment options? Expert Opin Pharmacother 2009;10:1-9.



Silverman EA, Sandhaus RA. Alpha-1 antitrypsin deficiency. N Engl J Med 2009; 360:2749 -2757.



Fairbanks KD. Tavill AS. Liver disease in alpha 1-antitrypsin deficiency: a review. American Journal of Gastroenterology. 2008; 103(8):2136-1241



Stoller JK, Piliang M. Panniculitis in alpha-1 antitrypsin deficiency. Clin Pulm Med 2008;15:113-117.



Stoller JK, Aboussouan LS. Alpha-1 antitrypsin deficiency. Lancet 2005;365:2225-2236.

Luisetti M, Seersholm N. Alpha1-antitrypsin deficiency. 1: Epidemiology of alpha 1-antitrypsin deficiency. Thorax 2004; 59(2):164-169.



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



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.

Resources

March of Dimes Birth Defects Foundation

1275 Mamaroneck Avenue

White Plains, NY 10605

Tel: (914)997-4488

Fax: (914)997-4763

Tel: (888)663-4637

Email: Askus@marchofdimes.com

Internet: http://www.marchofdimes.com



Alpha-1 Association

2937 SW 27 Avenue Suite 106

Alpha-1 Genetic Counselor: 1-800-785-3177

Miami, FL 33133

Tel: (305)648-0088

Fax: (305)648-0089

Tel: (800)521-3025

Email: info@alpha1.org

Internet: http://www.alpha1.org



American Liver Foundation

39 Broadway, Suite 2700

New York, NY 10006

USA

Fax: (212)483-8179

Tel: (800)465-4837

Email: http://www.liverfoundation.org/contact/

Internet: http://www.liverfoundation.org



American Lung Association

1301 Pennsylvania Ave NW

Suite 800

Washington, DC 20004

USA

Tel: (202)785-3355

Fax: (202)452-1805

Tel: (800)586-4872

Email: info@lungusa.org

Internet: http://www.lungusa.org



Children's Liver Disease Foundation

36 Great Charles Street

Birmingham, B3 3JY

United Kingdom

Tel: 01212123839

Fax: 01212124300

Email: info@childliverdisease.org

Internet: http://www.childliverdisease.org



Alpha-1 Foundation

2937 SW 27th Avenue Suite 302

Miami, FL 33133

USA

Tel: (305)567-9888

Fax: (305)567-1317

Tel: (877)228-7321

Email: info@alphaone.org

Internet: http://www.alphaone.org



Alpha-1 Research Registry

c/o Medical University of South Carolina

96 Jonathan Lucas St., Suite 812-CSB, MSC 630

Charleston, SC 29425-6300

USA

Tel: (843)792-0260

Fax: (843)792-0297

Tel: (877)886-2383

Email: alphaone@musc.edu

Internet: http://www.alphaoneregistry.org



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Madisons Foundation

PO Box 241956

Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.org



Alpha-1 Advocacy Alliance

PO Box 202

Wolftown, VA 22748

Tel: (540)948-6777

Fax: (540)948-6763

Tel: (866)367-2122

Email: webmaster@alpha1advocacy.org

Internet: http://www.alpha1advocacy.org



COPD-ALERT

3210 N. Leisure World Blvd.

Ste. 614

Silver Spring, MD 20906

Tel: (301)598-6693

Fax: (301)598-6926

Email: vlady@copd-alert.com

Internet: http://www.copd-alert.com



Childhood Liver Disease Research and Education Network

c/o Joan M. Hines, Research Administrator

Children's Hospital Colorado

13123 E 16th Ave. B290

Aurora, CO 80045

Tel: (720)777-2598

Fax: (720)777-7351

Email: joan.hines@childrenscolorado.org

Internet: http://www.childrennetwork.org



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