Alpha-1-Antitrypsin Deficiency

BACKGROUND:

Alpha-1-Antitrypsin (Alpha-1AT) deficiency is an autosomal recessive disorder commonly found in Caucasians of European descent. The major clinical manifestations are early onset emphysema (dramatically exascerbated by smoking) and liver disease. The prime function of Alpha-1-is as an inhibitor of the proteolytic enzyme elastase released from activated or disentegrating neutrophils. The lower respiratory tract is particularly vulnerable to low serum Alpha-1-levels resulting in progressive destruction of the alveoli and premature emphysema. Alpha-1-serum deficiency is caused by lack of secretion of Alpha-1-from hepatocytes, the major site of Alpha-1-synthesis. Intracellular accumulation of Alpha-1-results in hepatocyte injury, sometimes culminating in cirrhosis and hepatitis.

The incidence of the disease varies widely, from 1:2000 live births in Caucasians of European descent to very rare among Asian and African populations.

INDICATIONS FOR TESTING:

  • Confirmation of a clinical suspicion of Alpha-1-deficiency.

  • Carrier testing in individuals with a family history of Alpha-1-deficiency.

  • Carrier screening in high prevalence population groups.

SAMPLE REQUIREMENTS:

Blood: two 5 ml purple top (EDTA) vacutainers of whole blood (invert several times to mix). Forward within 48 hours at room temperature.

INTERPRETATION:

PCR based assays are used to detect two common mutations: Z (severe) and S (mild). These represent 99% of mutations found in Caucasians. Report will include assay results, background information, and a calculation of residual carrier risk if results are negative.

COUNSELING ISSUES:

  1. Individuals affected with Alpha-1-deficiency, especially smokers, accumulate lung damage that significantly shortens lifespan. The following table shows the cumulative probability of survival to specified ages.

     

    AGE (YEARS)

     

    30

    45

    60

    75

    Normal Non Smoker

    100%

    98%

    85%

    52%

    Normal Smoker

    88%

    80%

    62%

    N/A

    Alpha-1-Non Smoker

    86%

    82%

    60%

    8%

    Alpha-1-Smoker

    88%

    41%

    7%

    0%
    It is imperative that affected individuals be advised of the devastating effects of smoking.
  2. Among all emphysema patients in the United States, between 2% (all cases considered) to 18% (among younger patients) are Alpha-1-deficient, so this disease is the cause of a significant proportion of emphysema cases.

  3. Liver abnormalities are found in 17% of infants with Alpha-1-deficiency, some of whom will develop infantile cirrhosis. Approximately 1/3 will develop cirrhosis or hepatitis as adults.

 

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