Alpha 1-Antitrypsin Deficiency

Definition

Definition of Alpha 1-Antitrypsin Deficiency
Alpha 1-antitrypsin deficiency (a1-antitrypsin deficiency, A1AD or simply Alpha-1) is a genetic disorder caused by defective production of alpha 1-antitrypsin (A1AT), leading to decreased A1AT activity in the blood and lungs, and deposition of excessive abnormal A1AT protein in liver cells. There are several forms and degrees of deficiency, principally depending on whether the sufferer has one or two copies of the affected gene because it is an codominant trait. Severe A1AT deficiency causes panacinar emphysema or COPD in adult life in many people with the condition (especially if they are exposed to cigarette smoke), as well as various liver diseases in a minority of children and adults, and occasionally more unusual problems. It is treated by avoidance of damaging inhalants, by intravenous infusions of the A1AT protein, by transplantation of the liver or lungs, and by a variety of other measures, but it usually produces some degree of disability and reduced life expectancy.

Symptoms

Symptoms of Alpha 1-Antitrypsin Deficiency
Symptoms of alpha-1 antitrypsin deficiency include shortness of breath, wheezing, rhonchi, and rales. The patient's symptoms may resemble recurrent respiratory infections or asthma that does not respond to treatment. Individuals with A1AD may develop emphysema during their thirties or forties even without a history of significant smoking, though smoking greatly increases the risk for emphysema. A1AD also causes impaired liver function in some patients and may lead to cirrhosis and liver failure (15%). It is a leading cause of liver transplantation in newborns.

Causes

Causes of Alpha 1-Antitrypsin Deficiency
Mutations in the SERPINA1 gene cause alpha-1 antitrypsin deficiency.

The SERPINA1 gene provides instructions for making a protein called alpha-1 antitrypsin. This protein protects the body from being damaged by a powerful enzyme called neutrophil elastase. Neutrophil elastase is released from white blood cells to fight infection, but it can attack normal tissues (such as lung tissue) if not carefully controlled by alpha-1 antitrypsin. Mutations in the SERPINA1 gene can lead to a shortage (deficiency) of alpha-1 antitrypsin protein or an abnormal form of the protein that cannot control neutrophil elastase. Uncontrolled, neutrophil elastase destroys alveoli, which can lead to emphysema. The abnormal form of alpha-1 antitrypsin can also accumulate in the liver and may damage this organ.

Diagnosis

Diagnosis of Alpha 1-Antitrypsin Deficiency
A1AT deficiency remains undiagnosed in many patients. Patients are usually labelled as having COPD without an underlying cause. It is estimated that about 1% of all COPD patients actually have A1AT deficiency. Thus, testing should be performed for all patients with COPD, asthma with irreversible air-flow obstruction, unexplained liver disease, or necrotizing panniculitis. The initial test performed is serum A1AT level. A low level of A1AT confirms the diagnosis and further assessment with A1AT protein phenotyping and A1AT genotyping should be carried out subsequently.

As protein electrophoresis does not completely distinguish between A1AT and other minor proteins at the alpha-1 position (agarose gel), antitrypsin can be more directly and specifically measured using a nephelometric or immunotubidimetric method. Thus, protein electrophoresis is useful for screening and identifying individuals likely to have a deficiency. A1AT is further analysed by isoelectric focusing (IEF) in the pH range 4.5-5.5, where the protein migrates in a gel according to its isoelectric point or charge in a pH gradient. Normal A1AT is termed M, as it is migrates toward the center of such an IEF gel. Other variants are less functional, and are termed A-L and N-Z, dependent on whether they run proximal or distal to the M band. The presence of deviant bands on IEF can signify the presence of alpha 1-antitrypsin deficiency. Since the number of identified mutations has exceeded the number of letters in the alphabet, subscripts have been added to most recent discoveries in this area, as in the Pittsburgh mutation described above. As every person has two copies of the A1AT gene, a heterozygote with two different copies of the gene may have two different bands showing on electrofocusing, although a heterozygote with one null mutant that abolishes expression of the gene will only show one band. In blood test results, the IEF results are notated as, eg, PiMM, where Pi stands for protease inhibitor and "MM" is the banding pattern of that person.

Treatment

Treatment of Alpha 1-Antitrypsin Deficiency
In the United States, Canada, and several European countries, lung-affected A1AD patients may receive intravenous infusions of alpha-1 antitrypsin, derived from donated human plasma. This augmentation therapy is thought to arrest the course of the disease and halt any further damage to the lungs. Long-term studies of the effectiveness of A1AT replacement therapy are not available. It is currently recommended that patients begin augmentation therapy only after the onset of emphysema symptoms.

Augmentation therapy is not appropriate for liver-affected patients; treatment of A1AD-related liver damage focuses on alleviating the symptoms of the disease. In severe cases, liver transplantation may be necessary.

Prognosis

Prognosis of Alpha 1-Antitrypsin Deficiency
Some people with this deficiency will not develop liver or lung disease. However, emphysema and cirrhosis can be deadly.

Prevention

Prevention of Alpha 1-Antitrypsin Deficiency
Consult with your doctor.