In the United States, about 1 percent of emphysema cases are caused by an underlying genetic condition call alpha-1 antitrypsin deficiency.
That 1 percent equates to about 50,000 to 100,000 cases—most of which have not been diagnosed, says James F. Donohue, MD, professor of medicine at the UNC School of Medicine, who has been studying alpha-1 antitrypsin deficiency since the late 1980s and is on the leadership board of the national Alpha-1 Foundation.
Although research is ongoing on the manifestations of alpha-1 antitrypsin deficiency, it’s been established that the condition can result in serious lung disease in older adults or liver disease at any age.
What is alpha-1 antitrypsin deficiency?
Alpha-1 antitrypsin deficiency is an inherited condition that causes low levels of alpha-1 antitrypsin (AAT), a protein that protects the lungs from damage.
AAT is produced mainly in the liver. When a person has alpha-1 antitrypsin deficiency, the AAT in the liver is abnormal and not released from the liver at a normal rate. “It accumulates in the liver, where it’s toxic to the liver cell, and can ultimately lead to inflammation, cirrhosis, nonalcoholic fatty liver disease and liver cancer,” Dr. Donohue says.
In the lung, AAT is supposed to be protective. It blocks an enzyme released by neutrophils (white blood cells), called neutrophil elastase, in the lung. Because AAT isn’t released from the liver normally, it can’t properly protect the lungs from the enzyme. This causes an enzyme buildup that ultimately breaks down the structure of the lung and causes emphysema.
Two abnormal alpha-1 antitrypsin genes cause alpha-1 antitrypsin deficiency. Alleles—called S and Z—are most common. A person without alpha-1 will have two normal M genes (MM). People who experience alpha-1 most commonly have two abnormal Z genes (ZZ).
Carriers who have an MZ makeup are common. As long as they don’t smoke, they don’t have heightened health risks.
What are the clinical manifestations of alpha-1 antitrypsin deficiency?
Alpha-1 antitrypsin deficiency often causes pulmonary issues such as emphysema. These conditions usually develop later in life, which is why so many cases of alpha-1 antitrypsin deficiency go undiagnosed.
The damage done to the lungs causes an abnormal type of emphysema called panlobular emphysema, which manifests in the lower lobes.
“Emphysema is a silent disease that can explode on a patient around age 50 to 55,” Dr. Donohue says. The predominant symptom of emphysema is shortness of breath and air trapping, or hyperinflation, especially when exercising.
Another common lung disease caused by alpha-1 antitrypsin deficiency is non-cystic fibrosis bronchiectasis. This condition is marked by the widening and thickening of airways, which can cause mucus buildup.
Dr. Donohue says the non-CF bronchiectasis manifestation of alpha-1 antitrypsin deficiency is not as symptomatic as emphysema, though people who experience this are more susceptible to infection and have more mucus in the lungs.
Although lung disease is less common in younger people, severe asthma in young adults could indicate the presence of alpha-1 antitrypsin deficiency.
Unlike the late onset of pulmonary issues, problems relating to the liver can appear in infants, adolescents and adults. Childhood manifestations of alpha-1 antitrypsin deficiency are usually related to a biliary illness. If the condition worsens, it can escalate to liver disease and require a liver transplant.
“There are factors we don’t yet understand that leave some people with the same risk to have normal lungs and liver while others need transplants, so it’s a very variable clinical expression,” Dr. Donohue says.
Who’s at risk of developing lung or liver disease because of alpha-1 antitrypsin deficiency?
People with a family history of lung or liver disease are especially at risk of developing lung or liver disease as a result of alpha-1 antitrypsin deficiency. Smoking also increases your risk.
“People who smoke will have an accelerated decline in lung function, and some of those, maybe the majority, will get emphysema,” Dr. Donohue says. “Many people who do not smoke do very well. I’ve been doing this 40 years, and I’ve followed some people for many years who have had no difficulties or emphysema.”
That said, other factors that affect how alpha-1 antitrypsin deficiency manifests in both the lungs and liver are being researched.
“The cofactors are poorly understood. There are clearly other genes that are important. We’re trying to understand what those are,” Dr. Donohue says. “We still don’t understand the natural history of the liver with alpha-1. The lung was more easily recognized and more explosive in terms of its clinical manifestations. The seat of the problem is in the liver, and only in the last few years has there been a different focus trying to put more research into the liver.”
What treatment is available for alpha-1 antitrypsin deficiency?
Unfortunately, there aren’t many treatment options available. “The problem with this condition is that by the time the clinical features are prevalent and identified, the patient is usually pretty sick,” Dr. Donohue says.
Augmentation therapy, also called replacement therapy, is available to patients with two abnormal alpha-1 genes who are experiencing severe lung disease. The treatment is a blood replacement therapy that can be used with alpha-1 antitrypsin protein from the blood plasma of a donor or a blood product.
However, Dr. Donohue says the augmentation therapy is not common and is expensive—well over $100,000 a year.
For severe liver disease, a liver transplant can cure the illness.
Dr. Donohue recommends taking a lung- and liver-protective approach. “The important message is to be diagnosed and take control of the condition,” he says. “Take a preventive approach, and make sure you’re doing all the right things: good diet and exercise, avoid irritants and be monitored.” For the liver, this includes avoiding irritants such as alcohol and drugs.
It’s important to remember that alpha-1 antitrypsin deficiency cannot be diagnosed through a medical examination alone. Genotype and phenotype testing, which can be ordered through a blood test, are necessary to see if a person has the genetic abnormalities inherent to the condition. People who have lung or liver disease in their families or other risk factors should get tested.
Learn how to make a referral to UNC’s Pulmonary Diseases and Critical Care Medicine Department.