What is alpha-1 antitrypsin and alpha-1 antitrypsin deficiency (Alpha-1)?
Alpha-1 antitrypsin is a protein that is made within the liver and which is normally expelled by the liver into the bloodstream, where its presence can be measured by a blood test, called an "alpha-1 antitrypsin level."
The main function of the alpha-1 antitrypsin protein is to neutralize another protein (or enzyme) called neutrophil elastase, which is normally contained within one type of white blood corpuscle called the polymorphonuclear leukocyte, or PMN for short. Neutrophil elastase is a powerful enzyme which, upon release from the PMN, can degrade the walls of bacteria, rendering them harmless to the body. Normally, PMN’s circulate throughout the bloodstream and migrate to areas of infection or inflammation. In fact, contents of the PMN are responsible for the green color of pus, which of course accompanies infection or inflammation. When there is infection or inflammation within the lung, PMN’s go to the lung and, in defense of the body against infection or inflammation, release their contents of neutrophil elastase, which inactivate bacteria.
Unfortunately, neutrophil elastase can break down other structures beside the bacterial walls, one of which is a component of the supporting walls of the air sacs (or alveoli) in the lung, called elastin. When elastin breaks down, emphysema develops because the support structures of the walls of the air sacs break down. The result is a loss of air sacs, or alveoli, and a floppiness of the airways, which are normally held open by the elastic forces of the elastin in the walls. In this point-counterpoint wisdom of the body, alpha-1 antitrypsin serves the function of preventing the breakdown or digestion of the lung’s elastin by the released neutrophil elastase.
With this model in mind, we can explain the development of emphysema according to a hypothesis called the "protease-antiprotease" hypothesis. This hypothesis suggests that emphysema results from the unopposed activity of neutrophil elastase on the lung tissue. Under normal conditions, neutrophil elastase is inactivated by alpha 1-antitrypsin, but in conditions of excessive infection or inflammation when the burden of neutrophil elastase is high, or under conditions of alpha-1 antitrypsin deficiency, when the alpha-1 antitrypsin protective screen is depleted, unopposed action of neutrophil elastase can allow elastin breakdown and resultant emphysema.
Perhaps an easier way to visualize the role of alpha-1 antitrypsin in protecting the lung against emphysema is to think of the lung like an iron "jungle gym"—you know, the climbing bars that children play on in schoolyards or parks. Picture the metal bars of the jungle gym as the walls of the air sacs and the spaces between the bars as the air sacs (or alveoli) themselves. The neutrophil elastase in this metaphor is rain, which can break down the bars of the jungle gym by causing damaging rust over time. Alpha-1 antitrypsin can be considered rust-protectant paint, which coats the bars of the jungle gym and protects them against the degradative effects of the rain. However, under conditions of excessive rain or a shortage of paint, rust may develop sooner and the jungle gym will deteriorate sooner. In this metaphor, alpha-1 antitrypsin deficiency is having a shortage of rust-protectant paint, the result of which is an accelerated breakdown of the structure. If this paint shortage is made worse by excessive rain (or inflammation in the lungs), rust can develop even sooner.
Alpha-1 Antitrypsin Deficiency
Now, with this model of emphysema as a background, what causes Alpha-1? As mentioned, the protein alpha 1-antitrypsin is produced within the liver cells and secreted from the liver cell into the bloodstream. Although several different mechanisms can cause Alpha-1 deficiency, the most common type of deficiency (called the ZZ type) is due to the liver cell’s inability to secrete the protein, which congeals within the liver cell. The result is a liver cell with an excess of the unsecreted protein and levels of alpha-1 within the bloodstream that are too low to adequately protect the lung from the effects of neutrophil elastase. Thus, as a result of this deficiency of alpha-1, emphysema can occur and liver disease can result from the accumulation of the protein within the liver cell.
As mentioned, Alpha-1 is a genetic disease, meaning that it is inherited. What we inherit is the blueprint for making the alpha-1 antitrypsin protein. There are several different blueprints or types of alpha-1 antitrypsin. Though made in slightly different ways, most of these 100 variants function in the same way, they are secreted from the liver cell and provide adequate levels within the blood. However, some types of Alpha-1, most notably the so-called ZZ type, have an abnormal structure that prevents normal secretion from the liver cell and therefore very low levels within the blood. In particular, if normal blood levels of alpha-1 antitrypsin are between 100 and 220 milligrams per 100 milliliters (mg/dl), the levels in individuals with ZZ type Alpha-1 are only 10 percent of normal, roughly 10 to 25 mg/dl. Other abnormal blueprints that cause marked deficiency of alpha-1 in the blood exist, but are very rare. Thus, for all intents and purposes, severe deficiency of alpha-1 antitrypsin is almost always due to the ZZ type.
Evidence suggests that whenever the levels in the bloodstream are below 57 mg/dl, the risk of emphysema rises because 57 mg/dl is the minimum level necessary to provide adequate protection of the lung elastin from neutrophil elastase. Thus, individuals who inherit the ZZ type of Alpha-1 are at increased risk of developing emphysema, especially if they smoke, are exposed to second-hand smoke, have lung infections, or are exposed to dusty environments which can cause lung inflammation.
How is the ZZ type of Alpha-1 inherited?
When we are conceived, the egg and sperm merge, forming the embryo that grows into a fetus and a child. The egg and the sperm each carry one piece of genetic information for each of our traits from our mother and father, respectively. The blueprint for alpha-1 antitrypsin is one of these traits. If a Z blueprint is contributed from the mother and another Z blueprint for alpha 1 from the father, the child will have both Z blueprints and be a ZZ type, technically called a PI*ZZ homozygote.
The normal blueprint for the alpha-1 antitrypsin protein carries the name M, and the normal individual is MM. An individual who carries one Z blueprint (or allele) from one parent and one M blueprint from the other is called a PI*MZ heterozygote. Because the MZ heterozygote has one normal and one abnormal blueprint and because only the alpha-1 made with the Z blueprint congeals within the liver, the MZ individual will have an alpha-1 antitrypsin level in the bloodstream that is roughly half normal (approximately 70 to 140 mg/dl), but still above the 57 mg/dl "threshold" value at which emphysema risk rises above normal. Thus, individuals who are PI*MZ heterozygotes are felt not to be at risk of developing emphysema, but are at mild risk of developing liver disease because their liver cells will contain some accumulated alpha-1 (of the Z type) protein.
In terms of inheritance, a PI*ZZ parent will contribute the Z blueprint or allele to each child. A PI*MM parent will contribute the normal M blueprint (or allele) to each child, and a PI*MZ parent will have a 50 percent chance of contributing a Z blueprint and a 50 percent chance of contributing an M blueprint to each child. Thus, all children who are the products of one ZZ parent and one MM parent will be PI*MZ heterozygotes. All children who are the products of 2 PI*ZZ parents will be PI*ZZ. For children of one MZ parent and one ZZ parent, the situation is a bit more complex. Each child from such parents has a 50 percent chance of being an MZ heterozygote and a 50 percent chance of being a ZZ homozygote.
How common is Alpha-1?
Studies suggest that the frequency of ZZ type Alpha-1 is approximately 1 in 3,500 births in the United States. Thus, Alpha-1 occurs with the same frequency as cystic fibrosis. Notably, this frequency suggests there are 70,000 to 100,000 Americans with ZZ type Alpha-1. Yet, fewer than 10,000 such individuals have been diagnosed, meaning the majority of ZZ individuals are undetected.
Two possible explanations exist. First, we know that some ZZ individuals, especially non-smoking individuals, never develop emphysema or liver disease despite having the risk factor. Second, we know that some individuals are not diagnosed as having ZZ type Alpha-1 despite having suggestive problems, such as emphysema of early onset. Although we do not know what proportion of undiagnosed individuals are well vs. affected but undetected, we do know that under-recognition of Alpha-1 is common.
In one survey study, ZZ individuals with symptoms (largely shortness of breath) reported an average 7 year delay between first reporting this symptom and first being diagnosed with Alpha-1. Also, while about 25 percent of ZZ individuals reported being diagnosed by the first physician they saw, 43 percent reported seeing at least three physicians before the diagnosis was first made.
Studies also suggest that although most Americans are of the MM type, 2 to 3 percent are MZ. Also, of all patients with emphysema, 2 to 3 percent have emphysema on the basis of Alpha-1.
What are the features of emphysema due to Alpha-1?
Many features of emphysema due to Alpha-1 are similar to those of emphysema in individuals with normal alpha-1 antitrypsin levels. However, some features are distinctive in Alpha-1, and may help to suggest this genetic condition in affected individuals. First, although cigarette smoking clearly can accelerate the onset of emphysema in Alpha-1, emphysema can occur in never smokers with deficiency of alpha-1 antitrypsin. Although there are other illnesses in which emphysema can occur in the absence of smoking, non-smokers generally do not develop emphysema.
Second, the onset of emphysema may be much earlier in life in individuals with Alpha-1 than in smokers with normal Alpha-1 levels who develop emphysema. Specifically, emphysema generally presents in the mid- to late 60’s, whereas individuals with Alpha-1 may first experience symptoms of emphysema in their late 30’s to early 40’s.
A third distinctive feature of emphysema due to Alpha-1 is the pattern of emphysema on the chest X-ray or CT scan (another type of imaging study). Whereas emphysema of the "usual variety" in smokers affects the upper parts of the lung most prominently, the X-ray pattern in Alpha-1 is often just the reverse (i.e., the changes of emphysema on the chest X-ray or CT scan are more prominent at the bottom, or base, of the lung than at the apex). While this "rule" is often broken in practice, this "upside down" pattern of emphysema should prompt suspicion of Alpha-1 and lead to specific testing.
The fourth distinctive feature of Alpha-1 is that affected individuals may also be affected by the liver disease or by other conditions to which Alpha-1 predisposes. These include an unusual skin condition called panniculitis and a condition in which blood vessels in the kidney and lung become inflamed, called Wegener’s granulomatosis. Panniculitis is characterized by deep, weeping ulcers on the skin. Wegener’s granulomatosis may have many presentations, but is often characterized by kidney dysfunction, coughing up of blood, nodules on the chest X-ray, and sinus problems. Thus, individuals who have a combination of these conditions themselves or whose family histories show evidence of these conditions in other family members should be tested for Alpha-1.
Is there a connection between liver disease and Alpha-1?
Although emphysema is more common as a complication of alpha-1 antitrypsin deficiency, affecting up to 75 percent of individuals with known Alpha-1, liver disease may affect up to 30 percent. Liver disease may be of several different types: jaundice due to hepatitis occurring in newborns or children, cirrhosis or liver scarring occurring at any time in life, and liver cancer. Liver disease affecting children may have a variable course.
Usually, liver inflammation settles down and the individual is unaffected. Occasionally, the liver damage is progressive, leading to scarring and complications of cirrhosis. In fact, though uncommon, Alpha-1 is the second commonest reason for liver transplantation in children.
In adults, liver disease can come on unexpectedly, again causing chronic inflammation manifested by an elevation of liver tests, or liver scarring. Because cirrhosis can lead to serious problems of bleeding and mental confusion, cirrhosis from Alpha-1 may also lead to a recommendation for liver transplantation in adults.
How do you test for Alpha-1?
Testing for Alpha-1 involves two specific laboratory measurements. The first is the level of the alpha-1 antitrypsin protein in the blood, using the units of milligrams per 100 milliliters (mg/dl) as mentioned earlier. There is also a newer nomenclature using micromolar units.
When values are below the lower limit of the normal range for the laboratory, then deficiency may exist. Severe deficiency of the ZZ type—which is the commonest significant deficiency likely to be encountered—will generally show a serum level in the range of 10 to 30 mg/dl. The second test is to determine the so-called phenotype, which is a way of determining the genetic blueprint (e.g., PI*ZZ, PI*MM, PI*MZ, etc). Such phenotyping is more expensive (several hundred dollars versus about $100 for a level) and is needed only in circumstances where family testing is being undertaken, etc.
There are currently three fingerstick blood collection devices for Alpha-1 that are available free of charge to individuals who wish to be tested. Two are sponsored by pharmaceutical companies and the results are reported to the patient's healthcare provider that is filled out on the form sent along with the sample.
The other fingerstick device allows individuals to be tested on a confidential basis through the Alpha-1 Coded Testing Study at the Medical University of South Carolina. This is organized through the Alpha-1 Foundation.
There is also a new mouth swab test for Alpha-1 that can be obtained by physicians from LabCorp by calling toll-free 800-282-7300.
How is Alpha-1 treated?
Treatment of emphysema due to Alpha-1 is identical to that of usual "smoker's emphysema" in many ways. These general therapies for emphysema will be discussed first, followed by a discussion of specific treatment for Alpha-1, which is called augmentation therapy.
General Therapy for Emphysema
The most important step is to encourage quitting smoking. While the damage from smoking is permanent (because it involves the irreversible breakdown of the air sac walls), stopping smoking is associated with a slowing of the rate of decline of lung function to that of non-smokers. In other words, once you stop smoking, your rate of decline of lung function becomes that of a non-smoker and you won’t lose further lung function at an accelerated rate.
Other treatments often involve using various bronchodilators, which are medications intended to open up the air passages as much as possible in order to make available all the lung function an individual has. Bronchodilators are often inhaled, either by hand-held puffers called "metered dose inhalers" or by bulkier machines which aerosolize a liquid form of the bronchodilator medication. Other bronchodilators are sometimes prescribed in a pill form and may include theophylline-like medications or oral forms of the inhaled bronchodilators.
Oxygen is prescribed when the measured level in the bloodstream falls below a critical value. When this is observed, oxygen is recommended to be worn as close to 24 hours a day as possible.
Indeed, wearing oxygen close to 24 hours daily has been shown to be life-prolonging to individuals with emphysema when their blood oxygen levels breathing regular air fall below a threshold value.
Preventive therapies include vaccinations against a type of pneumonia called streptococcus and the influenza virus, the latter given yearly. Newly available are medications (such as zanamivir [Relenza] or oseltamivir [Tamiflu]) that are specifically active against the flu should infection occur.
Another important aspect of treating emphysema that causes a limitation of activity is pulmonary rehabilitation. By participating in a program including instruction, structured exercise, and group support, individuals with emphysema can achieve improved exercise capacity.
Finally, surgical therapies for emphysema include lung transplantation and lung volume reduction surgery (LVRS). Though different procedures, both of these operations are reserved for individuals with intolerable limitation from their emphysema and severely impaired lung function.
Lung transplantation usually involves the insertion of a single lung from a donor into one side of the chest cavity with removal of the damaged lung. As with all solid organ transplantation (e.g., kidney, liver, heart, etc.), the recipient must take potent medications lifelong to suppress the body’s rejection of the transplanted lung. Success rates are high and, among all individuals in need of lung transplant, are best for individuals receiving lungs for emphysema. Outcomes for individuals with alpha-1 are identical to those for individuals with "usual" emphysema, with survival rates approximately 60 to 70 percent at five years in the largest and best transplant centers.
Lung volume reduction surgery is a newly revived surgical procedure that involves shaving part of the damaged lung in order to allow the remainder of the lung to expand and function better. Although early reports have shown promise, the efficacy of LVRS is currently the subject of discussion. Experience with LVRS for Alpha-1 is relatively sparse, with the few available studies suggesting that benefit may be conferred, though perhaps smaller than that seen in individuals with usual emphysema. Specifically, lung function can improve in some individuals by up to 50 percent. To date, not everyone has experienced benefit and, in the context that the operation carries about a 3 to 5 percent risk of death, further clarification of exactly who will benefit is being evaluated. Furthermore, the duration of benefit in individuals with emphysema due to Alpha-1 seems to be shorter (e.g., 1 to 2 years) than in those with usual emphysema.
Augmentation Therapy for Alpha-1 Antitrypsin Deficiency
In addition to the aforementioned general therapies for emphysema, treatment for individuals with emphysema due to Alpha-1 may include one specific treatment that is reserved for Alpha-1. This therapy is called augmentation therapy and involves the administration, currently by vein, of a purified form of the alpha-1 antitrypsin protein on a regular basis (e.g., usually weekly or monthly) in order to raise the levels in the bloodstream above the "protective threshold" value of 57 mg/dl. In this regard, augmentation therapy can be thought of as being similar to insulin therapy in diabetes. The condition results from the lack of this material and the treatment involves restoring the normal levels of the missing material by administering it.
Studies to date have shown that intravenous augmentation therapy has so-called biochemical efficacy (i.e., that administering purified alpha-1 antitrypsin derived and purified from the blood of many donors can raise the bloodstream levels while preserving the ability of the infused material to inactivate neutrophil elastase). Although definite proof that intravenous augmentation therapy improves outcomes in recipients (i.e., slows the rate of decline of lung function, improves longevity) is not available, several supportive studies do suggest that such treatment is clinically effective.