Alpha 1 Antitrypsin Disease

Alpha 1-antitrypsin disease is a genetic disease that is caused by a relative lack of production of alpha 1-antitrypsin, a molecule that is particularly effective in the lungs and in the bloodstream.  The protein becomes excessive in the liver.  The disease varies from person to person but severe alpha 1-antitrypsin disease almost always triggers a person to have chronic obstructive pulmonary disease or emphysema.  Liver disease in children to adults is also common in the disease. Sometimes more unusual conditions occur.   Briefly, the condition is treated by infusions of alpha 1-antitrypsin, liver or lung transplantation.  Even so, there is some disability in the individual and life expectancy is less than normal.
Those with alpha 1-antitrypsin disease often show signs of wheezing, shortness of breath, rhonchi and other noises within the lungs. Symptoms appear to be those of asthma but they do not tend to get better with treatment.  Young people with alpha 1-antitrypsin disease develop emphysema in their thirties or even in their forties, whether or not they were smokers.  Poor liver function occurs in most involved patients and liver cirrhosis or liver failure are common.  In fact, it is not out of the question to need to have a liver transplantations in patients as young as newborns. 

Pathophysiology
The molecule alpha 1-antitrysin is created in the human liver and one of its jobs is to protect the lung tissue from the enzyme neutrophil elastase, which is an enzyme that destroys connective tissue.  Those with alpha 1-antitrypsin disease can have wide variations in the amount of A1AT in their bloodstream.  The more of the molecule the less serious the disease.  Some patients are only symptomatic if they are also smokers. Those with less than 15% A1AT levels, are much more likely to develop emphysema in their youth and liver cirrhosis.  Smoking inactivates alpha 1-antitrypsin and makes the disease much more difficult to tolerate.

Modes of Treatment
One of the primary modes of treatment of alpha 1-antitrypsin disease is to use donated human plasma and provide infusions of A1AT.  This is believed to halt the progress of the disease.  Unfortunately, long term studies on the use of A1AT are not available.  Many patients begin the intravenous treatment only after the emphysema symptoms begin to develop.  Augmenting a patient with A1AT is not believed to be an appropriate treatment for those patients who have liver involvement.  Instead, the liver disease is treated and, in some cases, liver transplants are needed.    Some recent forms of therapy include using recombinant A1AT and inhaled forms of the medication. 
One method of treatment is to use the antioxidant glutathione, which is diminished in many forms of lung disease. The dose is given by means of bronchioalveolar lavage. 

Epidemiology
Those at highest risk for alpha 1-antitrypsin disease tend to live in Northern European countries, Iberian countries, and Saudi Arabian countries.  About 4% carry the allele and between 1 in 625 to 1 in 2000 are homozygous for the disease. Mutations in a gene called SERPINA1 lead to alpha 1-antitrypsin disease. SERPINA1 is the gene that protects the body from damage by the neutrophil elastase enzyme.  Neutrophil elastase comes from white blood cells and is design to fight infection.  In high doses, it can attack normal tissue as well.  Mutations in the SERPINA1 gene lead to a shortage of alpha 1-antitrypsin protein. The uncontrolled neutrophil elastase enzyme wrecks lung alveoli, leading to the disease of emphysema. 
The disease itself is inherited by an autosomal codominant pattern. This means that two different versions of the same gene can be shown and both versions contribute to the genetics of the disease.  The most common gene type is the SERPINA1 gene, known as M.  When healthy, it makes enough alpha 1-antitrypsin protein.  The S allele of the gene produces moderately low levels of alpha 1-antitrypsin disease.  The Z allele of the gene produces very little alpha 1-antitrypsin disease. A person born with a ZZ combination fares the worst with alpha 1-antitrypsin disease. 

Related Conditions
The following conditions should cause one to suspect alpha 1-antitrypsin disease:  liver cirrhosis, Wegener’s granulomatosis, emphysema, asthma, pancreatitis, bronchiectasis, gallstones, autoimmune hepatitis, cancer of the gallbladder, lung, liver, bladder and lymphoma.