Elastin is the lungs' basic structural material, providing the bulk of the overall elastic framework and the alveoli walls. Elastase is an essential enzyme for maintaining healthy lungs because it digests ineffective, aging elastin fibers so they can be replaced by new ones. (It is called a protease enzyme because it digests a protein.) Alpha1-antitrypsin (AAT for short)another enzyme normally abundant in the lungsdigests excess elastase, which otherwise would start eating into healthy elastic tissue. If for some reason there is not enough AAT to keep the amount of elastase under control, it starts destroying healthy elastic tissue faster than it can be replaced. This is the beginning of emphysema.
Although with most emphysema patients the culprit is cigarettes, a small percentage develop this chronic lung disease because they inherited one or two defective genes for producing the AAT enzyme. People with two defective genes produce almost none at all. People with one defective and one healthy gene produce this regulatory enzyme, but either in very small amounts, or in an altered form that functions poorly. The American Lung Association reports that approximately 1 in every 2,500 people in the United States has some form of AAT deficiency. Based on the total U.S. population, this amounts to 100,000 people. The Alpha1 Associationthe national support and advocacy organizationis in the same ballpark. They estimate that 80,000 to 100,000 men, women, and children are affected by AAT deficiency, and they point out that only a fraction of them have been diagnosed. The Alpha 1 Association nicknames the disease A1AD, and patients often refer to themselves as alphas.

Our 31 chromosomes together contain about 100,000 genesthe blueprints for all our inherited characteristics and physiologic functions. We have two sets of 31 chromosomes, one from each parent. The AAT gene resides on chromosome 14. It is nicknamed the PI geneshort for protease inhibitorand designated 14q32.1. (Since there are still many genes with unidentified functions, we give every gene an "address" that pinpoints its location, and we also give names to those whose function we already know.) AATthe most important member of the family of protease enzymesis produced primarily in the liver. The rest of it is produced by certain white blood cells, and by cells in the intestines and kidney. Everyone has two AAT genesone on the chromosome 14 passed on from the mother, and one on the fathers chromosome 14. Most people have two normal genes, some have two defective genes, and some have one of each. Defects are the result of mutations that affect a gene's ability to function properly. Although at least 90 different harmful mutations have been identified in this gene, the "Z" type is overwhelmingly the most common.

As a general rule, for any important functionlike AAT productiona pair of defective genes wreaks havoc. When just one gene in the pair is defective, the consequence varies. Some functions require only one healthy genewith the second acting as back-up just in case something goes wrong with its partnerand then a defective gene simply remains silent. But for functions requiring two healthy genesand AAT is one of theseeven one defective gene causes trouble. The enzyme is produced, but either in an inadequate amount or as a malfunctioning enzyme.

The majority (95%) of patients with the most severe deficiency have inherited the Z variant from each parent. The remaining 5% of these patients represent about 20 other mutation types, and include a few people with one normal gene. The person with two defective genes produces almost none of this critical regulatory enzymefar too little to control the destruction of elastin. Most of these people eventually develop emphysema. (They are also at risk of developing chronic liver disease, especially children and adults older than 50. Liver pathology develops in about 10% of these children and 25% of these older adults.) With one defective gene, a person's liver typically still produces roughly 75% of the normal amount. So the subtle problems this may cause don't often emerge as definable symptoms. According to both the World Health Organization and the Alpha 1 Association, only a small proportion of the number of people estimated to have this deficiencyboth severe and less severehave been diagnosed.

Cigarette smoke both seriously speeds up the destruction of lung tissue and transforms a single-gene defect into a far more significant health problem. Because smoking irritates the lungs, white blood cells are attracted to the site to repair the damage. As they happen to be the same white blood cells that produce elastase, this substantially adds to the excessive amount of elastase already bathing the interior of the lungs. Adding insult to injury, oxidants in the smoke itself inactivate much or all of the AAT that might still be present. In A1AD people who smoke, emphysema symptoms are usually obvious by age 35. Not smoking gives them another 10 years before reaching this point.

Although little is known yet about the harm caused by environmental air pollution to A1AD people, it is likely that such oxidants as ozone, sulfur dioxide, and nitrogen oxides also speed up the progression of emphysema in these cases. Similarly, the existence of respiratory infections in early childhood also seems to be a risk factor for early development of emphysema in these people.