Alpha-1 antitrypsin

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Alpha-1 antitrypsin


Alpha-1 antitrypsin is one of the most common inherited diseases in the Caucasian population. The most common symptom is lung disease (emphysema). People with alpha-1 antitrypsin may also develop liver disease and/or liver cancer. The disease is caused by a deficiency in the protein alpha-1 antitrypsin, which is why the condition is sometimes called alpha-1 antitrypsin deficiency. Other names include anti-elastase, antitrypsin, and ATT. The development of lung disease is accelerated by harmful environmental exposures, such as smoking tobacco. Alpha-1 antitrypsin is inherited. The age of onset, rate of progression, and type of symptoms vary both between and within families.


The protein alpha-1 antitrypsin is a protease inhibitor, which means that it inactivates other proteins called proteases. This is an important function, as proteases themselves disable proteins. In our bodies the levels of proteases and their inhibitors are balanced so that proteases can perform their functions but not over-per-form, which leads to problems.

A protease called elastase is the most important target of alpha-1 antitrypsin. Elastase protects the lungs against bacteria and other foreign particles. However, if the action of elastase is not kept in check, elastase destroys lung tissue. Alpha-1 antitrypsin ensures that elastase is not overactive.

Individuals with alpha-1 antitrypsin have inadequate levels of the protein alpha-1 antitrypsin. Thus, certain proteases (especially in the lungs) are overactive, which leads to emphysema and sometimes to liver disease. Alpha-1 antitrypsin is made mostly in the liver.

Some alpha-1 antitrypsin proteins are abnormal in addition to being deficient. These abnormal proteins may not move from the liver to the blood stream correctly. The build-up of the proteins in the liver may lead to liver disease. Also, the abnormal proteins may not neutralize elastase as effectively. Thus, people with alpha-1 antitrypsin have fewer proteins; those that they do have do not work as effectively.

Genetic profile

The genetics of alpha-1 antitrypsin are complicated. Scientists have identified many different forms of the gene that codes for the alpha-1 antitrypsin protein. This protein is often called Pi and the gene called PI, for protease inhibitor. One form of the gene, which scientists call Z, or PI Z, greatly reduced the amount of the active Pi protein. Because every person inherits one of each gene from his or her mother, and another copy of each gene from his or her father, everyone has two copies of every gene. People who have two copies of the PI Z gene have 85% less alpha-1 antitrypsin protein. These people have only 15% of the normal level of protein. The protein that they do have does not function as well as the normal protein. People who have one PI Z gene and one normal PI gene have about 60% of the normal level Pi protein. Other forms of the alpha-1 antitrypsin gene are associated with more or less severe deficiencies in protein.

Two other common forms of the Pi protein are called S and M. Pi M is the normal protein and PI M is the normal gene. The Pi M protein has many subtypes within the population, designated M1, M2, etc. A few abnormal alpha-1 antitrypsin genes also have unique names. The PI S gene is slightly abnormal, but not as abnormal as PI Z. Individuals with one PI S gene and one PI Z gene have approximately 38% functioning of the Pi protein (Pi SZ).

The inheritance of alpha-1 antitrypsin is autosomal recessive. This means that a person with alpha-1 antitrypsin has inherited one abnormal gene from each of his or her parents. The parents are most likely carriers, meaning they each have one normal gene and one abnormal gene. Two carriers have a one in four chance to have an affected child with each pregnancy. However, not all people with alpha-1 antitrypsin develop symptoms. Whether and when a person with two abnormal alpha-1 antitrypsin genes develops symptoms is related to the degree of harmful exposures, such as tobacco smoke. A person who is affected with alpha-1 antitrypsin is only at risk to have an affected child if the child's other parent is a carrier.

Although the inheritance of alpha-1 antitrypsin is autosomal recessive, the activity of the protein is equally determined by the gene inherited from either parent. For example, if a gene inherited from one parent codes for a protein with 100% activity, and the gene inherited from the other parent codes for a protein with 0% activity, the offspring would have 50% protein activity. The physical expression of the genes is autosomal recessive, but each gene has an equal effect on the protein activity—neither gene is dominant over the other gene. The gene for alpha-1 antitrypsin is on chromosome 14. More than 90 different forms of the gene have been identified.


Alpha-1 antitrypsin is most common in Caucasians, especially those of Northern European descent. Alpha-1 antitrypsin is less common in populations of Asian, African, and American Indian descent. Approximately one in 2,500 Caucasians have two Z genes. These individuals account for 1% of all emphysema patients. Because people with one PI Z gene and one other deleterious PI gene may also have symptoms, the number of people at risk to have alpha-1 antitrypsin associated lung disease is greater than one in 2,500. Approximately one in 20 Caucasians has one Z gene and one normal gene. The number of Caucasians with one S gene and one normal gene is even higher. Approximately one in 1,000 Caucasians of Northern European descent have two S genes (and no normal alpha-1 antitrypsin gene).

Signs and symptoms

The main symptom of alpha-1 antitrypsin is a risk for early-onset, rapidly progressive emphysema. People with alpha-1 antitrypsin who smoke tobacco are at especially high risk. Emphysema is chronic lung disease that begins with breathlessness during exertion and progresses to shortness of breath at all times, caused by destructive changes in the lung tissue. The risk for liver disease in adults is increased, as is the risk for hepatocellular carcinoma (liver cancer ). Some children with alpha-1 antitrypsin develop liver disease as well. Individuals with alpha-1 antitrypsin are also at risk for chronic obstructive lung disease and reactive airway disease (asthma ). Chronic obstructive lung disease is decreased breathing capacity, which may be caused by emphysema but also has other underlying causes.

Lung disease

Approximately 60–70% of the people with two PI Z genes develop chronic lung disease. Shortness of breath with exertion may begin before the age of 40 years and progress rapidly to incapacitating emphysema. Life expectancy may be reduced by 10–15 years and is reduced further if people with two PI Z genes smoke tobacco. A portion of the people with two PI Z genes never develop chronic lung disease.

The age of onset and severity of symptoms associated with alpha-1 antitrypsin are quite variable, even within the same family. Environmental exposures significantly effect whether a person will develop symptoms. Smoking puts individuals with alpha-1 antitrypsin at much greater risk to develop emphysema. The already abnormal and deficient Pi Z protein functions 1,000 times less effectively in smokers. Researcher Ronald Crystal states, "Cigarette smoking renders an already poorly defended lung completely defenseless." People with alpha-1 antitrypsin who are not exposed to harmful environmental factors are less likely to develop emphysema. If people with two PI Z genes stop smoking before they develop lung disease, their life expectancy increases and the risk of lung disease decreases.

Individuals who have one abnormal gene with very little protein function and one gene with somewhat reduced protein function may also at risk for chronic obstructive lung disease. It is possible that people with one Z gene and one normal gene are also at risk to develop chronic lung disease if they are exposed to harmful environmental factors such as tobacco smoke. The age symptoms begin in this group would be later than that seen in people with two abnormal genes. Some researchers disagree, stating that people with PI SZ and PI MZ genes are not at significant risk for lung disease.

Liver disease

The risk of liver disease and liver cancer are increased in individuals with alpha-1 antitrypsin. Babies and children with alpha-1 antitrypsin may have abnormal liver function and inflammation. The abnormal liver function they develop is called cholestasis, which is when the liver stops secreting a digestive fluid called bile. A build-up of bile causes cholestatic jaundice (yellowing of the skin). These abnormalities sometimes progress to liver disease and liver failure, which is fatal without a liver transplant. In other babies and children, liver function returns to normal.

A small number of adults with alpha-1 antitrypsin develop liver disease, and some develop liver cancer. The age at which the liver disease begins, the rate at which it progresses, and the stage at which it is usually diagnosed are quite variable. Adults with alpha-1 antitrypsin who had liver abnormalities as children may be at increased risk to develop liver disease or liver cancer. People with one normal PI gene and one PI Z gene may be at increased risk for liver disease.

The likelihood that a child or adult with alpha-1 antitrypsin will develop liver disease can be predicted to some degree based on which change in the gene (mutation) they have as well as their family history. The risk that a baby with two Z genes will develop significant liver disease is approximately 10%. However if a person has a family history of alpha-1 antitrypsin with liver disease, this risk may be higher. Males (both adult and children) develop liver disease more often than females. Alpha-1 antitrypsin is the most common genetic cause of liver disease in infants and children. Researchers do not know why some people with alpha-1 antitrypsin develop progressive liver disease and many others do not. The liver disease appears to be related to abnormal antitrypsin protein remaining in the liver instead of being secreted.


Alpha-1 antitrypsin may be suspected in a newborn with cholestatic jaundice, swollen abdomen, and poor feeding. In later childhood or adulthood, fatigue, poor appetite, swelling of the abdomen and legs, or abnormal liver tests may trigger the need for testing. The diagnosis of alpha-1 antitrypsin is based on measurement of antitrypsin (Pi) in the blood. If levels of Pi are deficient, genetic studies may be performed to determine which abnormal forms of the gene are present. The Pi protein can also be studied to determine which type a person has. Prenatal diagnosis is available, however, it is recommended that parental genetic studies precede prenatal testing to ensure accurate interpretation of results.

Levels of antitrypsin protein in the blood may be normal in individuals who have one PI Z gene and one normal gene, and in individuals who have one PI S gene and one PI Z gene. Studying the Pi protein will more accurately diagnose these individuals.

Lung disease in people with alpha-1 antitrypsin is diagnosed by the same methods used to diagnose lung disease in people who do not have alpha-1 antitrypsin. These studies include breathing tests such as total lung capacity and pulmonary function tests. Total lung capacity is measured with a device called a spirometer. Pulmonary function tests measure oxygen/carbon dioxide exchange by determining the amount of air exhaled, the time to exhale, and the efficiency of oxygen transport. X rays and other studies may also be performed.

Liver disease in children and adults with alpha-1 antitrypsin is diagnosed by the same methods used to diagnose liver disease in people who do not have alpha-1 antitrypsin. Liver function studies include tests measuring two liver proteins called serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT). SGOT is sometimes called aspartate transaminase (AST), and SGPT is sometimes called alanine aminotransferase (ALT). Studies may also be performed looking for deposits within the cells of the liver called inclusions.

Once the diagnosis of alpha-1 antitrypsin has been made, it is important to share this information with relatives related by blood, especially parents and children. These relatives may also have alpha-1 antitrypsin. If they know that they have it before they develop lung disease, they can take preventative measures such as avoiding exposure to smoke and other lung toxins. Some organizations have recommended that individuals with asthma be tested for alpha-1 antitrypsin.

Treatment and management

Although alpha-1 antitrypsin cannot be prevented, many of the condition's consequences can be prevented. People with alpha-1 antitrypsin should not smoke cigarettes and should not be exposed to smoke or other lung irritants. Respiratory infections should be treated promptly because they increase the level of harmful elastase in the lungs. Some doctors recommend avoiding alcohol and oxidants; keeping hepatitis A and B vaccinations, pneumococcal vaccinations, and influenza shots up-to-date; and preventing hepatitis C exposure.

Protein augmentation

Treatment is available if individuals with alpha-1 antitrypsin develop lung disease. Infusion of alpha-1 antitrypsin protein into the bloodstream may halt or slow progression of respiratory problems. The protein is put into a blood vein weekly, biweekly, or monthly. Treatment with the replacement protein may not be effective if tissue damage to the lungs is severe. This is often called augmentation therapy. This therapy is safe and people who receive it have few adverse reactions. However, some researchers are not convinced that it is an effective treatment.

People with alpha-1 antitrypsin who have diminished lung air capacity but no other symptoms may be given prophylactic replacement antitrypsin infusions. In the year 2000, the success of prophylactic treatment has not been confirmed. The controversy over augmentation therapy may be resolved in 2001. A task force currently addressing this issue and others is scheduled to publish treatment and standard of care recommendations at that time.

Treatments in development

People who have two abnormal PI genes have reason to be hopeful that effective treatments may be available by 2010. The Pi protein may be available in an inhaled form in the first few years of the new millennium. Biotechnology based treatments such as aerosols that deliver the normal gene to lung tissue are being studied. Lung transplant may be an option in the future.

Liver disease treatments

Some doctors advocate regular monitoring of liver function in elderly patients with alpha-1 antitrypsin. In most people with alpha-1 antitrypsin, an initial liver function evaluation will be performed but it will only be repeated if the person has symptoms. Augmentation therapy (replacing the protein in the blood) does not effectively treat the liver disease. In 2001, gene therapy for liver disease is not possible.

The treatment for children with alpha-1 antitrypsin who develop liver disease is a liver transplant. Alpha-1 antitrypsin is a common reason for liver transplant in the pediatric population. If the new liver is from a donor with normal alpha-1 antitrypsin, the new liver will have normal, functional protein after the transplant.


Individuals with alpha-1 antitrypsin who have never smoked nor been exposed to other respiratory irritants have the best prognosis. They may never develop lung disease. If they do develop lung disease, the age of onset is usually later than that of smokers—10 or more years later. Prognosis is improved if people with alpha-1 antitrypsin stop smoking before the onset of lung disease.

The lung disease people with alpha-1 antitrypsin develop typically progresses rapidly. Affected individuals may progress from decreased respiration during exertion to incapacitation in five years. Smoking cessation and prompt treatment are critical. Prompt treatment with replacement protein improves prognosis. Some scientists recommend delaying treatment until the affected person has quit smoking.

Prognosis of infants with liver disease is poor. If a donor is found and transplant successful, the new liver has the alpha-1 antitrypsin gene of the donor. Therefore, if the liver transplant is successful the prognosis related to alpha-1 antitrypsin is very good.

A great deal of research is done on the prevention and cure of alpha-1 antitrypsin. In 1996, the World Health Organization sponsored a meeting of experts who study the disease. The experts outlined specific topics to be researched, which included studying treatments. In 1997, 12 countries with registries of alpha-1 antitrypsin patients formed an international registry. This will make it easier for researchers to complete studies involving large numbers of patients, which are absolutely necessary to answer research questions (especially treatment questions). Pharmaceutical companies are also studying new treatment options. Researchers are hopeful about new treatments that may become available. Even with new medicines, the most important treatment for alpha-1 antitrypsin will probably be prevention.



Crystal, Ronald G., ed. Alpha 1-Antitrypsin Deficiency. Lung Biology in Health & Disease Series, vol. 88. New York: Marcel Dekker, Inc., 1995


Alpha 1 National Association. 8120 Penn Ave. South, Suite 549, Minneapolis, MN 55431. (612) 703-9979 or (800) 521-3025. [email protected]. <>.

Alpha One Foundation. 2937 SW 27th Ave., Suite 302, Miami, FL 33133. (305) 567-9888 or (877) 228-7321. mserven <>.

Alpha to Alpha. RR#5 Box 859, Warsaw, MO 65355. (660) 438-3045. <>.

AlphaNet. (800) 557-2638. <>.

American Liver Foundation. 75 Maiden Lane, Suite 603, New York, NY 10038. (800) 465-4837 or (888) 443-7222. <>.

American Lung Association. 1740 Broadway, New York, NY 10019-4374. (212) 315-8700 or (800) 586-4872. <>.


"Alpha1-Antitrypsin Deficiency or Inherited Emphysema." Fact sheet. National Jewish Medical and Research Center. <>.

"A1AD Related Emphysema." Fact sheet. American Lung Association. <>.

Michelle Queneau Bosworth, MS, CGC