What is alpha-1-antitrypsin deficiency?

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Alpha-1-antitrypsin deficiency (AATD) is caused when the liver cannot produce sufficient amounts of alpha-1-antitrypsin protein, which inactivates other proteins, including elastase. Elastase protects the lungs, but if it becomes overactive, it destroys lung tissue. People who inherit two copies of the Z form of the SERPINA1 gene are most affected by this disease.
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Risk Factors

AATD affects mostly Caucasians of northern European descent. Men and women are affected in equal numbers; however, males with this disease are more likely to develop liver problems than are females with this disease. Nongenetic factors such as smoking and exposure to lung-harming chemicals or fumes affect the severity of this disease.

Etiology and Genetics

The SERPINA1 (formerly PI) gene that causes this disease is on chromosome 14. This gene has three common forms—M, S, and Z—with M being the normal form. The severity of the disease hinges on which forms of these genes are inherited. These gene forms all have subforms (M1, M2, S1, S2, Z1, Z2, etc.) that also affect the severity of the disease expression. As of 2009, more than 120 forms of this gene had been identified. A common genetic mutation that creates the Z form happens when two amino acids switch places on a chromosome (lysine replaces glutamic acid at position 342 on the SERPINA1 gene on chromosome 14).

AATD is carried in an autosomal codominant pattern, where a person must inherit an abnormal gene from each parent, each of whom has the disease or is a carrier. The most severe gene form is Z, and if a person inherits two Z forms of this gene, his or her disease may be very severe, where the liver produces only about 10 to 20 percent of the normal levels of alpha-1-antitrypsin protein. The gene form S is the next most severe form, and a person with one Z and one S form generally produces about 38 percent of the normal levels of this protein. M is the normal form of the gene, and a person with one Z and one M may produce about 60 percent of normal protein levels, depending on the subform of the gene inherited. These genes are codominant, meaning that they each affect the level of protein; for example, someone with an MZ gene type has a protein level somewhere between a person with an MM gene type and a person with a ZZ gene type.

People who have at least one M (normal) gene type generally produce enough alpha-1-antitrypsin to somewhat protect their lungs and may never exhibit any disease symptoms. These people are at greatest risk from outside factors; for example, someone with an MZ gene type may develop lung disease only if he or she smokes. Even some people who have two abnormal genes do not exhibit symptoms of this disease, depending on the subforms of the genes inherited. The subforms of these genes and how they affect the manner in which disease is expressed is a focus of research in this field.


In adults, this disease is characterized by breathlessness, wheezing, and early and rapid progressive lung disease, particularly in a person who does not smoke. Liver disease, such as jaundice, in children or adults may also be a symptom of AATD.

Screening and Diagnosis

The lung component of AATD is screened and diagnosed with the same tools, such as pulmonary function tests or lung capacity tests, as are used for other lung diseases. The liver component is also screened and diagnosed with standard liver function tests. The actual diagnosis of AATD is based on a blood test that measures the blood levels of this protein. Genetic testing can determine which gene types one carries, if any, and thus determine carrier status.

Treatment and Therapy

Slowing the progress of lung disease is the first-line treatment. Immediate smoking cessation is essential, and limiting exposure to secondhand tobacco smoke and other lung irritants can also improve outcomes. Treatment may include inhaled bronchodilators or steroids, pulmonary rehabilitation, and oxygen therapy.

Treatment may involve infusions of alpha-1-antitrypsin directly into the bloodstream. This treatment is not effective if lung tissue is extremely damaged, nor does it alleviate any liver problems. Treatment for AATD liver disease is a liver transplant. Lung transplant may also be a treatment option.

Treating respiratory infections quickly and receiving influenza and pneumococcal vaccinations may be helpful in managing lung disease. Avoiding alcohol, minimizing exposure to hepatitis C, and receiving hepatitis A and B vaccinations may help minimize liver problems.

This disease is often misdiagnosed and treated as another lung disease such as asthma or chronic obstuctive pulmonary disease (COPD); minimal response to the standard therapies for these diseases may be an indication of AATD.

Prevention and Outcomes

There is no way to prevent this disease in an affected individual, though its severity can be limited by quitting smoking or avoiding irritants. Life expectancy depends on the severity of symptoms. Those who smoke or are exposed to lung irritants have much less successful outcomes than those who do not. The outlook for patients who progress to emphysema or cirrhosis is grim.

Genetic testing is recommended for at-risk individuals and their partners, as well as for siblings of an affected individual, to determine whether they will pass the genetic condition onto their children. If both prospective parents have the M and Z gene forms, for instance, there is a 25 percent chance that their child will be severely affected (have the ZZ combination) and a 50 percent chance that he or she will be a carrier (have the MZ combination). Prenatal diagnosis may also be warranted in cases where a couple have already had an infant with severe liver disease.


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