Alpha-1 antitrypsin deficiency, or alpha-1 for short, is a common genetic disorder that predisposes affected individuals to lung disease, as well as liver disease and a variety of other medical conditions.1 Although alpha-1 is an inherited condition, some individuals with alpha-1 may lead perfectly healthy lives, unaffected by their genetically altered alpha-1 antitrypsin gene. Alpha-1 is common in that there are between two and 10 times as many people in the United States with alpha-1 as there are people with cystic fibrosis.2 Approximately one of every 14 Americans carries at least one abnormal gene for alpha-1.3 And 1% of patients with chronic obstructive pulmonary disease (COPD) have undetected alpha-1 (R.A.S., unpublished data, 2010).4 In spite of this knowledge, less than 5% of individuals with alpha-1 have been identified.
This disparity between the condition’s prevalence and its diagnosis is due solely to lack of testing. A simple, inexpensive blood level test will reveal if someone has severe deficiency, and even genotyping can be performed at no cost using a finger-stick and mail-in kits provided by companies that make alpha-1 therapeutics or by the not-for-profit Alpha-1 Foundation.
One reason that testing is not done often enough is the false assumption that there is nothing to be done for those diagnosed with alpha-1. As shown in the Table below, the diagnosis of alpha-1 should trigger a variety of interventions, from education of the patients and their families; to routine specific follow-up; to reduction of risks factors; and, in individuals with lung disease due to alpha-1, to the consideration of weekly augmentation therapy infusions.1,5 This article will briefly review the diagnosis of alpha-1, the interventions that are helpful, and the rationale for treatment.
Making the Diagnosis
The diagnosis of alpha-1 is simpler than most health care providers think, and yet there are complexities that are not immediately obvious. When alpha-1 was first discovered in the early 1960s,6 it was an abnormal serum protein electrophoresis (SPEP) that was the key. Several families with early-onset, apparently hereditary emphysema were found to lack the alpha-1 band in their SPEP testing, and investigators soon learned that the missing band was made up almost entirely of a single protein that had already been named antitrypsin—thus the name alpha-1 antitrypsin. But SPEP is not considered an accurate measure of the amount of alpha-1 antitrypsin protein in serum, so more specific level testing was developed.
Today, virtually any clinical laboratory can perform an alpha-1 antitrypsin level on serum—and for a modest price. Level testing can provide an accurate diagnosis of severe alpha-1 antitrypsin deficiency. The complexity enters when one learns that there have been more than 100 different mutations of the alpha-1 antitrypsin gene identified since the first article describing the deficiency was published in 1963.
About one third of these mutations lead to some deficiency of alpha-1 antitrypsin in the blood. But several lead to the production of dysfunctional proteins that appear at normal blood levels. In addition, when screening family members for the presence of one or two abnormal genes for alpha-1, a serum level may not reveal whether a brother, sister, or other relative is the carrier of only a single abnormal gene, because these individuals may have levels of protein in the blood that are within or near the normal range.
To allow for detection of these various combinations of genes, two additional testing methods have been widely employed. One is known as Pi-typing and the other is genotyping. Pi-typing, previously known as alpha-1 phenotyping, looks at the circulating alpha-1 antitrypsin protein using an isoelectric focusing (IEF) gel, and, based on the pattern of bands that appear, one can tell which genes coded for those proteins. These IEF gels (and the electrophoretic methods that preceded IEF) led to a nomenclature for alpha-1 antitrypsin proteins and genes known as the Pi system, for protease inhibitor system.7 The normal gene and protein was named “M” or PiM and the most common deficient gene was named Z or PiZ. Thus, a severely deficient individual with alpha-1 is often found to have two of these common abnormal genes and is PiZZ. A sibling who inherited only one abnormal gene might be PiMZ.
This naming system has been carried over into genotyping, a technique that evaluates the gene for alpha-1 antitrypsin rather than the circulating protein. It is reasonable to assume that, since alpha-1 is a genetic condition, genotyping would be the gold standard of testing. That assumption would be wrong. Genotyping for alpha-1, as currently performed at commercial and research labs in the United States, looks for the two most common abnormal genes associated with alpha-1, the Z gene and the S gene on each of the two strands of DNA of an individual being tested. If one or the other is present, it is reported as one would expect: PiZ or PiS. But if neither is detected, the result on that strand of DNA is assumed to be PiM or normal, ignoring the other 30 to 40 known abnormal genes. This is not an unreasonable assumption, considering that these other genes are extremely rare. But it has led to some incorrect diagnoses.
The take home message is that it is wise to test using more than two or three of the available methods to make an accurate diagnosis.5 There are several free test kits available to detect alpha-1 that use both blood levels and genotyping, performed on dry blood spots obtained by finger-stick. This is a highly accurate method for detecting both severely deficient individuals and carriers of a single abnormal gene.
A recent study completed at 18 academic pulmonary function laboratories in the United States had respiratory therapists offer free testing to every patient referred for pulmonary function testing who met GOLD stage II, III, or IV criteria for COPD (postbronchodilator FEV1 of less than 80% and an FEV1/FVC of less than 70%) (R.A.S., unpublished data, 2010). If the patient consented to participate, the RT performed a finger-stick and spotted the blood onto the special test kits for level and genotype testing. The results of about 3,500 such tests showed that nearly 1% of unselected patients with COPD have undetected severe alpha-1 antitrypsin deficiency. If this percentage is true for all of the more than 12 million individuals with COPD in the United States, then more than 120,000 individuals with COPD have undetected alpha-1.
After the Diagnosis
Learning the diagnosis of alpha-1 can be quite stressful. The diagnosis not only affects the patient just diagnosed but also has implications for their parents, siblings, children, and other relatives (see Table at right). This stress is magnified if the information provided does not reflect our latest understanding of alpha-1. Many patients still are told that they have a fatal condition and they should “get their affairs in order.”
Over the past several decades, we have learned a number of important facts about alpha-1:
- As mentioned earlier, many individuals with severe deficiency will never be affected in any medical way by this condition.
- Even if an individual with alpha-1 has lung disease or liver disease, elimination of environmental risk factors can slow or halt the progression of disease.
- For lung disease due to alpha-1, there is specific therapy, known as augmentation, that will likely slow or halt the progression of emphysema.
- Overall, the survival of individuals with alpha-1 has been steadily improving.
- In the most severe cases of lung or liver disease, organ transplantation has become increasingly successful.
Among the items above, the one that is usually unfamiliar to health care providers is augmentation therapy. Currently, augmentation therapy is the intravenous administration of purified human alpha-1 antitrypsin protein prepared from the plasma of healthy donors. It is generally administered at a dose of 60 mg/kg body weight each week. Studies are currently under way to evaluate whether this therapy might be administered directly into the lungs by nebulization.
The mechanism of lung injury in alpha-1 is well understood. An enzyme that can destroy the elastic connective tissue in the lungs is released by the body’s own white blood cells when they are fighting infection or participating in inflammation. This enzyme is known as neutrophil elastase. Alpha-1 antitrypsin is the body’s primary inhibitor of neutrophil elastase. The goal of augmentation therapy is to “augment” the amount of circulating alpha-1 antitrypsin bathing the lungs and protect the lung tissue from further injury. Augmentation therapy would not be expected to reverse any damage that has already occurred but rather would protect the remaining uninjured tissue.
As this description suggests, augmentation therapy is not indicated for people without lung disease, since they may never develop lung injury. In addition, this therapy should not be used to treat the liver disease of alpha-1, which is caused by an entirely different mechanism. Augmentation therapy is currently manufactured by four different companies under four different brand names. There is no evidence that any individual product provides any specific therapeutic or safety benefits over any of the others.
The Role of the RT
There has been a growing reliance on the RT community in both diagnosis and follow-up of alpha-1. The study performed in PFT labs across the country, mentioned earlier, documented the ability of RTs to identify appropriate patients for testing, provide appropriate informed consent, and perform the testing itself. Going forward, each institution will need to evaluate the potential role that RTs can play in detection of alpha-1.
Regardless of the role played by RTs in alpha-1 detection, all RTs need to maintain their knowledge of alpha-1 and its treatment because of the growing patient population they will see who have been diagnosed with this condition. There is a spectrum of risks associated with development of disease in alpha-1, and reducing these risks is an important aspect of appropriate care. Studies have shown that it is extremely rare to find an individual with lung disease due to alpha-1 who had not been exposed to cigarette smoke, either as a smoker or as a child growing up in a household where parents smoked.8 This emphasizes the importance of smoking prevention and/or cessation for both the individual with alpha-1 and close family members. Additional modifiable risk factors include occupational exposures to dusts and fumes and frequent respiratory infections. Immunizations against influenza and pneumococci are important in the alpha-1 population.
Once an individual with alpha-1 is identified and family testing is begun, it is likely that immediate family members may be found who are carriers of a single abnormal gene for alpha-1. The risks and treatment of such carriers are still being studied. The best information to date suggests that carriers who are smokers have about 2.3 times the risk of developing lung disease compared with the general population of smokers.9 Thus, smoking prevention and cessation become the keys in preventing disease in this population. The story of alpha-1 and the lung destruction it allows has been a potent and effective incentive for smoking cessation.
Alpha-1 antitrypsin deficiency is a common, hereditary disorder that can lead to pulmonary emphysema, liver disease, and other medical conditions in affected individuals. It is much more common than previously thought, yet it remains undiagnosed in the vast majority of individuals with the disorder. The RT has had a growing role in the diagnosis and follow-up of individuals with alpha-1. Knowledge of this condition by both the individual with alpha-1 and that individual’s health care providers is the best way to prevent or slow disease.
Robert A. Sandhaus, MD, PhD, is professor of medicine and director, Alpha-1 Program, National Jewish Health, Denver. He is also medical director, Alpha-1 Foundation and AlphaNet, Miami.
- Silverman EK, Sandhaus RA. Clinical practice. Alpha1-antitrypsin deficiency. N Engl J Med. 2009;360:2749-57.
- de Serres FJ. Worldwide racial and ethnic distribution of alpha1-antitrypsin deficiency: summary of an analysis of published genetic epidemiologic surveys. Chest. 2002;122:1818-29.
- de Serres FJ, Blanco I, Fernandez-Bustillo E. Genetic epidemiology of alpha-1 antitrypsin deficiency in North America and Australia/New Zealand: Australia, Canada, New Zealand and the United States of America. Clin Genet. 2003;64:382-97.
- Lieberman J, Winter B, Sastre A. Alpha 1-antitrypsin Pi-types in 965 COPD patients. Chest. 1986;89(3):370-373.
- American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168:818-900.
- Laurell CB, Eriksson S. The electrophoretic alpha-1-globulin pattern of serum in alpha-1-antitrypsin deficiency. Scand J Clin Lab Invest. 1963;15:132-40.
- Fagerhol MK, Laurell CB. The Pi system-inherited variants of serum alpha 1-antitrypsin. Prog Med Genet. 1970;7:96-111.
- Mayer AS, Stoller JK, Vedal S, et al. Risk factors for symptom onset in PI*Z alpha-1 antitrypsin deficiency. Int J Chron Obstruct Pulmon Dis. 2006;1:485-92.
- Hersh CP, Dahl M, Ly NP, Berkey CS, Nordestgaard BG, Silverman EK. Chronic obstructive pulmonary disease in alpha1-antitrypsin PI MZ heterozygotes: a meta-analysis. Thorax. 2004;59:843-9.