• Disease Overview
  • Synonyms
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
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  • Complete Report

Alpha-1 Antitrypsin Deficiency


Last updated: November 19, 2020
Years published: 1985, 1988, 1990, 1991, 1993, 1996, 1997, 1998, 1999, 2001, 2002, 2005, 2008, 2011, 2014, 2017, 2020


NORD gratefully acknowledges James Stoller, MD, MS, Chairman and Jean Wall Bennett Professor of Medicine, Education Institute, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine, for assistance in the preparation of this report.

Disease Overview

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, now called polyangiitis with 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 can lead to progressive emphysema and is accelerated by smoking, some occupational exposures, and likely by other genetic modifiers of this risk which remain incompletely understood.

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  • A1AD
  • AATD
  • genetic emphysema
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Signs & Symptoms

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). Some individuals with severe deficiency of A1AT never develop emphysema and have a normal life, especially if they never smoke. Individuals affected by A1AD often 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 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 if the lung disease is advanced.

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 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 abdominal cavity (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).

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 A1AT genotypes, 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 serosanguineous (serum and blood) drainage and accompanying systemic symptoms, including fever.

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

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A1AT is caused by mutations in the SERPINA1 gene that is responsible for production of the alpha-1 antitrypsin protein. Normally, 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 (enzymes that break down proteins). In addition, abnormal A1AT protein can accumulate in the liver and cause scarring damage. Over 150 different mutations in the SERPINA1 gene have been identified to date, with the most common termed S and Z, whereas the normal version (allele) of the gene is termed M. The S allele causes serum levels of A1AT to be moderately low and the Z allele is associated with very low A1AT levels in the serum (~10-15% of normal). Other rare variants, called null, are associated with the complete absence of A1AT in the bloodstream, because no protein is produced.

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 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 altered gene and to 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 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, especially if they smoke. If an individual receives one S allele and one Z allele (SZ), they are also considered to be at increased risk to develop chronic obstructive pulmonary disease if they smoke.

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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 A1AD go unrecognized, the disorder is very much under-diagnosed. Estimates suggest that only 10% or fewer of these estimated 100,000 individuals with severe deficiency of A1AT have been diagnosed, with the others either having chronic obstructive pulmonary disease (COPD) that has not been recognized to be on the basis of A1AD or being unaffected. Several lines of evidence show that A1AD is under-recognized: 1. Many A1AD individuals experience long delays (i.e., mean of 5 – 8 years) between initial symptoms (often shortness of breath) and initial diagnosis of A1AD, and 2. Affected individuals often see many physicians with A1AD-related symptoms before initial diagnosis is made. That under-recognition persists is suggested by the fact that the diagnostic delay intervals remain long even in more recently diagnosed individuals.

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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 [usually for the Z and S alleles and sometimes for additional alleles like the F and I alleles and some others on commercial tests]). In some instances, further testing to sequence the A1AT gene is needed to establish a firm diagnosis (i.e., mapping all the chemical elements [called nucleotides] that make up the A1AT gene).

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 (i.e., siblings, children, and parents), 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 of panniculitis is aroused by a suggestive history and physical examination, the diagnosis of panniculitis is made by biopsy specimens of the skin lesions and blood tests to determine the level of circulating A1AT and the genotype.

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Standard Therapies

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 or phosphodiesterase 5 inhibitors 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 (usually once weekly), long-term infusion into the veins of deficient individuals of purified, pooled human plasma-derived A1AT. Currently, six drugs for augmentation therapy have received approval by the U.S. Food and Drug Administration: Prolastin, Aralast, Aralast NP, Zemaira, Prolastin-C, and Glassia, of which the latter four are currently available. The best available evidence suggests that augmentation therapy may help slow the progression of lung damage due to A1AD. Augmentation therapy does not treat A1AD-related liver disease.

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. As such, LVRS is rarely recommended for patients with A1AD.

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 who otherwise qualify as candidates for such surgery.

No specific therapy is available for the liver disease associated with A1AD, though animal studies have shown promise for several drugs that can increase the liver’s ability to break down unsecreted A1AT (e.g., rapamycin and carbamazepine) and have prompted research studies in A1AD individuals. Similarly, other approaches currently under investigation regard agents that will decrease the production of the abnormal Z protein by liver cells, which could conceivably lessen the liver risk, though of course much more study is needed before any conclusion can be offered regarding these currently research-based approaches. Currently, management of A1AD-associated liver disease 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. Transplantation of a normal liver into an individual with A1AD should correct the liver abnormalities and restore the blood levels of A1AT to normal. At the same time, transplantation carries some risk related to the procedure itself and to the suppressed immunity from drugs taken to prevent rejection of the transplanted organ.

Genetic counseling is recommended for patients and their families.

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Clinical Trials and Studies

Promising prospects include gene therapy (by intramuscular or intrapleural injection of a virus carrying the normal human A1AT gene), administration of augmentation therapy by inhalation, modified approaches to intravenous augmentation therapy with recombinant molecules that may require less frequent infusions, the administration of agents that turn off the production of mutant A1AT protein in the liver, and the synthesis of normal A1AT in human or yeast cells for subsequent use in augmentation therapy. Early studies of so-called “corrector molecules” which may favorably allow better secretion of A1AD from the liver and of small molecules that prevent the misfolding of A1AD within the liver cell are under way. Also, studies examining the effect of a seizure drug called carbamazepine on liver disease in A1AD individuals and studies assessing differing doses of intravenous augmentation therapy are currently under way.

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 NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact: www.centerwatch.com

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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
[email protected]

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

Strnad P, McElvaney NG, Lomas DA. Alpha-1 antitrypsin deficiency. N Engl J Med 2020; 382:1443-1455.

Brantly M, Campos M, Cross C, Goodman K, Hogarth K, Knight S, Stocks J, Stoller JK, Strange C, Teckman J. Clinical practice guideline: The diagnosis and management of alpha-1 antitrypsin deficiency in the adult. JCOPDF 2016; 3(3):668-682.

Greene C, Marciniak S, Teckman J, Ferrarotti I, Brantly M, Lomas D, Stoller JK, McElvaney N. Alpha-1 antitrypsin deficiency. Nature Reviews Disease Primers 2016; 2:1-17.

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Stoller JK. Detecting alpha-1 antitrypsin deficiency. Annals Am Thorac Soc 2016; 13 (Suppl 4): S317 – S325.

Chapman KR, Burdon JGW, Piitulainen E, et al. Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2015; 385: 360 – 368 ( DOI: http://dx.doi.org/10.1016/S0140-6736(15)60860-1)

Mohanka M, Khemasuwan D, Stoller JK. A review of augmentation therapy for alpha-1 antitrypsin deficiency. Expert Opin Biol Ther 2012 Jun; 12(6):685-700.

Stoller JK, Aboussouan L. Concise clinical review: Alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med 2012;185:246-259.

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 OpinPharmacother 2009;10:1-9.

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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. Alpha-1 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.

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