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Last updated: 3/21/2024
Years published: 1985, 1988, 1990, 1991, 1993, 1996, 1997, 1998, 1999, 2001, 2002, 2005, 2008, 2011, 2014, 2017, 2020, 2024
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.
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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 what was previously called Wegener’s granulomatosis, now called polyangiitis with granulomatosis (GPA). 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 the skin and A1AD can also cause liver scarring because the A1AT protein can accumulate inside the liver cell. 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 which are found in the walls of the air sacs of the lung, also called alveoli. Over years, this destruction can lead to progressive breakdown of the walls of the air sacs which is emphysema and is accelerated by smoking, some occupational exposures and likely by other genetic modifiers of this risk which remain incompletely understood.
Lung disease
Alpha-1 antitrypsin deficiency-associated lung disease is characterized by progressive degenerative and destructive changes in the lungs (emphysema, commonly of the so-called 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 (i.e., long intervals before their first symptom of A1AD and their first being diagnosed with A1AD) and have many visits to different health care providers before the diagnosis is made for the first time.
Breathing tests (pulmonary function tests) may show reduced expiratory air flow, hyperinflation and low diffusing capacity; a CT scan of the chest may show loss of lung tissue that may not be apparent on a regular chest X-ray or on breathing test results. An abnormal level of oxygen in the arterial blood (arterial hypoxemia), with or without an elevated level of carbon dioxide in the blood, 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 patients), 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 test values and symptoms of cholestasis (e.g., jaundice, dark urine, pale stools and itching). Other symptoms may include enlarged liver, stomach 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 blood tests, severe liver dysfunction and a condition called portal hypertension which can result in bleeding from enlarged veins in the stomach or food tube (esophagus). Individuals with liver disease from A1AD may also become easily fatigued, experience decreased appetite, swelling of the legs or abdomen, enlargement of the liver (hepatomegaly), accumulation of fluid in the abdomen and legs and a general increase in 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, elastography, magnetic resonance imaging [MRI], 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 non-smoking individuals who may escape the associated emphysema. Because the mechanism of the liver disease (i.e., accumulation of too much unsecreted A1AT protein within the liver cells) differs from that of the emphysema (i.e., proteolytic damage to the lung support tissues because there is too little A1AT in the lung), liver disease may occur separately from the emphysema (though both may co-occur in some individuals).
Panniculitis
Some patients with A1AD develop 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 types (called genotypes), not limited to those genotypes associated with severe deficiency of A1AT.
Panniculitis seems to develop in only a small fraction of patients with A1AD. The cause of panniculitis and why it occurs so uncommonly is unknown, though the observed favorable effects of increasing serum levels of A1AD with infused, purified A1AD protein (so-called “augmentation therapy”) suggests that panniculitis may be caused by 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. 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. Severe tissue damage can accompany panniculitis. In some patients, direct trauma often precedes the development of the lesions.
Alpha-1 antitrypsin deficiency (A1AT) is caused by disease-causing variants in the SERPINA1 gene that is responsible for producing the alpha-1 antitrypsin protein. Normally, this protein is produced in the liver and released into the bloodstream and functions to protect the body from the neutrophil elastase enzyme which is contained within the white blood cells called neutrophils. Neutrophil elastase is released from white blood cells to fight infection, but it can attack normal tissues (especially the lungs) if not tightly controlled by alpha-1 antitrypsin.
Variants in the SERPINA1 gene result in production of an abnormal protein that can get trapped in the liver, resulting in low serum and lung levels of A1AT (that can predispose to lung breakdown by neutrophil elastase and other proteolytic enzymes, i.e., enzymes that break down proteins). In addition, abnormal A1AT protein can accumulate in the liver and cause scarring damage. A1AT also appears to have anti-inflammatory effects independent of its anti-neutrophil elastase activity. In summary, without enough functional alpha-1 antitrypsin, neutrophil elastase destroys alveoli and causes lung disease. Abnormal alpha-1 antitrypsin can also accumulate in the liver and damage this organ.
The most common version (allele) of the SERPINA1 gene, called M, produces normal levels of alpha-1 antitrypsin. Most people in the general population have two copies of the M allele (MM) in each cell. People who have two M alleles (MM) have normal levels of serum AAT in the blood.
Other versions of the SERPINA1 gene lead to reduced levels of alpha-1 antitrypsin.
The S allele causes blood levels of A1AT to be moderately low and the Z allele is associated with very low A1AT levels in the blood (~10%-15% of normal).
People who have two copies of the Z allele (called ZZ) have severe deficiency of A1AT and are at high risk of developing emphysema and liver disease. People with the SZ combination have an increased risk of developing lung disease, particularly if they smoke. Other rare variants, called “null”, are associated with the complete absence of A1AT in the bloodstream, because no protein is produced. Over 150 different variants in the SERPINA1 gene have been identified to date. In summary:
Environmental factors such as exposure to tobacco smoke, chemicals and dust, likely impact the severity of alpha-1 antitrypsin deficiency.
AATD 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) and, therefore, both alleles contribute to the genetic trait.
Worldwide, it is estimated that 185 million people have one copy of the S or Z allele and one copy of the M allele in each cell (MS or MZ). People who are MS or MZ are said to be “carriers” for the condition or are called “heterozygotes MS or MZ” (heterozygous means having different versions called alleles of a gene) and most likely will not have AAT deficiency.
For two heterozygous MZ parents (who have a normal M allele and “carry” the Z allele):
The risk is the same for males and females.
In the less frequent cases in which one parent is homozygous ZZ and one parent is heterozygous MZ, the risk to each child of being homozygous ZZ and to be affected with AATD is 50%.
Alpha-1 antitrypsin deficiency is a disorder that occurs most frequently in Americans of Northern or Central European descent, affecting approximately 100,000 Americans. However, because most patients with A1AD go unrecognized, the disorder is very much under-diagnosed. Estimates suggest that only 10% or fewer of these estimated 100,000 Americans 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 caused by 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 the diagnosis is made. That under-recognition persists today is suggested by the fact that the diagnostic delay intervals remain long even in more recently diagnosed individuals and are no shorter currently than they were in the mid 1990’s.
The diagnosis of A1AD is based on a low concentration of A1AT in the blood in combination with a high-risk phenotype (demonstrated by a test called isoelectric focusing) or by genotype analysis (i.e., detecting specific abnormal alleles [usually the Z or S alleles and sometimes for additional abnormal alleles called the F and I alleles]). In some instances, further testing to sequence the SERPINA1 gene is needed to confirm the diagnosis. Testing for at-risk family members and prenatal and preimplantation genetic testing are possible once the SERPINA1 variants have been identified in the family.
Because A1AD often goes unrecognized, official guideline documents recommend that all individuals with fixed airflow obstruction on breathing tests (called spirometry) should be tested for the disorder. Also, all first-degree relatives of individuals found to have severe A1AD (i.e., siblings, children, and parents) should be tested for A1AD, as should individuals with panniculitis, and individuals with unexplained liver disease or bronchiectasis.
This disorder may be especially 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 are 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.
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 some cases) specific A1AT treatment called augmentation therapy (see below). 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, periodic pneumococcal, respiratory syncytial virus (RSV) and COVID vaccination 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 AAT that comes from blood of donors, which is highly purified to extract the A1AT. Currently, four drugs for augmentation therapy have been approved by the U.S. Food and Drug Administration (FDA): Prolastin-C, Aralast, Zemaira, and Glassia. The best available evidence suggests that augmentation therapy may help slow the progression of lung damage due to A1AD. However, because the liver disease associated with A1AD results from the presence of too much A1AT in the liver cells (rather than a deficiency of the A1AT protein, as in the lung) augmentation therapy does not help A1AD-related liver disease and is not recommended for this indication.
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 be less effective in 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. A non-surgical approach to achieve lung volume reduction (as by placing one-way valves into the airways of the lung through a bronchoscope) has been described in a small number of patients with A1AD with encouraging but currently inconclusive results.
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 yet 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, but 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.
Promising prospects include gene therapy (by intramuscular, intrapleural injection, or inhalation 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 people with A1AD 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.alpha1.org or call the Foundation at (877) 228-7321.
Contact for additional information about alpha-1 antitrypsin deficiency:
James K. Stoller, MD, MS
Jean Wall Bennett Professor of Medicine
Cleveland Clinic
9500 Euclid Ave.
Cleveland, OH 44195
(216) 444-1960
[email protected]
TEXTBOOKS
Kohnlein T, Welte T, (eds). Alpha-1 antitrypsin Deficiency: Clinical Aspects and Management. 2nd edition. Bremen: UNI-MED; 2010.
JOURNAL ARTICLES
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.
Hatipoglu U, Stoller JK. Alpha-1 antitrypsin deficiency. Clin Chest Med 2016; 37:487-504.
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. https://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 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. 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.
Campbell EJ. Alpha-1 antitrypsin deficiency: incidence and detection program. Respir Med. 2000;94:S18-21.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
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View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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