Monday, October 19, 2009

Do You Know Alpha-1 Antitrypsin Deficiency?

Let me confess this upfront. Until I met John Walsh at the 2008 Genetic Alliance conference, I was not familiar with the genetic disorder called Alpha-1 Antitrypsin Deficiency (AATD). John is one of the founders and President of AlphaNet. Since then I have learned that AATD, a genetic mutation, reduces the levels of a protective protein in the bloodstream. AAT deficiency can lead to chronic obstructive pulmonary disease (COPD), specifically emphysema, and liver disease.

John had attended a presentation I gave on improving the use of family health history and genetic/genomic data in the electronic health record. Later I was both surprised and honored when he invited me to become a member the AlphaNet board of directors. So when I saw that Alpha-1 Antitrypsin Deficiency was added in April of this year to my 23andMe Carrier Status report, I thought the timing was providential.

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As I have new opportunities to met people with Alpha-1, they would always ask if I have been tested to see if have the mutation. I hadn’t until the 23andMe result appeared. The test most people take is a simple finger-stick test for blood. But you can also get tested by genotyping, which is how I learned of my AAT deficiency carrier status.

23andMe told me that an estimated one out of every 5,000 - 7,000 North Americans has AAT deficiency. Interestingly, in Scandinavia the numbers are higher. One in every 1,500 to 3,000 people there is affected. These numbers go higher when you take into account the people who have AAT deficiency, but have not been diagnosed.

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The main versions of the gene that encodes AATD are PI*M (the normal version), PI*S, and PI*Z. A person inherits a copy of the gene from each parent, producing six possible combinations: MM, MS, MZ, SS, SZ, and ZZ. Something I learned from 23andme - In addition to the PI*M, PI*S, and PI*Z versions of the gene for AAT, there are more than 20 known rare mutations that can lead to AAT deficiency.

The PI*Z form of the gene is the most severe mutation; the ZZ genotype accounts for 95% of AAT deficiency. People with the SZ genotype are at an increased risk for COPD, particularly if they smoke. The MZ genotype causes only mild reduction in AAT protein levels, but may lead to decreased lung function in smokers.

Difficult Diagnosis

The AlphaNet website tells us that Alpha-1 patients experience difficulty and delay in getting properly diagnosed. Clinical research studies have shown that once a patient develops symptoms, it takes an average of seven years and visits to five different doctors before the diagnosis of Alpha-1 is correctly made. I have met Alpha’s that confirm this. Many non-smoking Alpha’s are of accused of smoking by their doctor. About 3% of all people diagnosed with COPD may have undetected Alpha-1.

For treatment of lung disease caused by AAT deficiency, intravenous alpha-1-antitrypsin augmentation therapy, annual flu vaccination and a pneumococcal vaccine every 5 years are recommended. Relief of breathlessness may be obtained with long-acting bronchodilators and inhaled corticosteroids. Both end-stage lung and liver disease can be treated by organ transplantation. In AATD patients with cirrhosis of the liver, the prognosis is generally grave.

The AlphaNet Community

I began working with AlphaNet a year ago. I learned that one of the many things AlphaNet does is provide disease care coordinators for more than 7,000 people with Alpha-1. Their website further explains that “AlphaNet Coordinators are spread across the United States and subscribers to AlphaNet are assigned to a specific AlphaNet Coordinator based upon geographical location. Each AlphaNet subscriber is contacted at least monthly by his or her AlphaNet Coordinator. The AlphaNet Coordinator provides support, education and assistance with augmentation therapy infusion issues and supplies.” Since 1997, AlphaNet has donated $25 million to the Alpha-1 Foundation, which performs research to cure AAT deficiency.

More information I learn from 23andMe includes -

· Not everyone with AAT deficiency will have symptoms, leading some researchers to suggest that additional genetic factors other than mutations in the gene that encodes AAT may be involved.
· Between 15% and 19% of adults with AAT deficiency develops cirrhosis of the liver after age 50.
· The donor liver following liver transplantation will make normal AAT protein and actually cure the deficiency in the rest of the body.

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Family History

A paper on Alpha-1 antitrypsin deficiency was published this summer in the New England Journal of Medicine. One of the authors, Dr. Robert A. Sandhaus, is also a board member and Medical Director of AlphaNet. The article states that “AAT deficiency is recognized in less than 10% of persons in whom a diagnosis would be expected on the basis of screening studies in the general population. The diagnosis of AAT deficiency is generally made after the identification of COPD or liver disease or after the deficiency has been diagnosed in a family member”.

The authors recommend that a family testing discussion be held in the initial evaluation of the newly diagnosed patient. A diagnosis of Alpha-1 could impact family including brothers, sisters, children, grandchildren, and possibly extended family members.

To assist in finding those who are still undiagnosed, Intermountain Healthcare’s Clinical Genetics Institute is designing a study using an internet-based, patient-entered family health history program. Both the software program and the research study are under development, but we hope to find that computerized family health history tools can be effective screening methods to identify and treat those families that might be at risk for an inherited, familial disease for which they are not aware. The earlier the detection, the less damage the disease will have done.

Perspective from a medical geneticist

Traditional vs. Predisposition Genetic Testing

The two results from testing discussed this month, BRCA and alpha-1 antitrypsin (AAT), represent much more traditional types of genetic testing than the predisposition testing we’ve written about in most of the posts. In contrast to the BRCA testing which was limited to only three mutations (or the Cystic Fibrosis gene CFTR where only one mutation is tested), the AAT test results report all of the recommended clinically important mutations in this gene. Grant does an excellent job of describing the disease and its implications.

From my perspective, the challenge that hasn’t been adequately met in practice is testing of individuals who are symptomatic. As Grant points out, we are not doing a very good job of identifying the disease in symptomatic individuals. In 2008, Hogarth and Rachelefsky published a review in the journal Chest that looked at testing and screening for AAT deficiency. (reference below) They highlight 4 interventions that could be used if the disease was identified early. These include: smoking prevention/cessation; minimizing the hazards of occupational respiratory pollutants; the opportunities to receive augmentation therapy; and the potential for family planning and guided genetic counseling/testing. Thus we have a situation where we can definitively characterize the results of the mutation testing; we can identify individuals at risk; we can initiate preventive measures in those at risk and start treatment in symptomatic patients. This in some ways represents an ideal genetic test.

Genetic Testing for Symptomatic Patients

While there have been some suggestions that population screening (at least in Caucasians) for AAT mutations would be beneficial, the consensus has been that this approach would be too expensive. In addition, there are many individuals who carry disease causing mutations who never develop symptoms. That said, we’re doing a very poor job testing individuals who are symptomatic, despite professional guidelines supported by strong evidence that recommend testing all individuals with emphysema, COPD, or asthma with airflow obstruction not completely reversible with the use of bronchodilators; all individuals with unexplained liver disease; asymptomatic subjects with persistent obstruction found on pulmonary function test findings and with identifiable risk factors; and adults with necrotizing panniculitis.

Informed Consumers

So it certainly appears that there would be a role for informed consumers to be able to access testing given that health care professionals are not doing an adequate job. Interestingly this has been studied in AAT, including testing of minors. (see references below). These tests seem to be well accepted. Nearly 80% of current smokers indicated that they were highly likely to stop smoking if they were ZZ. Most individuals (but not all) said they would share the results of testing with their physician, however a small number would not want the result placed in their medical record because of concerns about privacy.

The U.S. Center for AIR is performing testing under a research protocol to learn more about the risks and benefits of direct-to-consumer testing for AAT deficiency. This type of research is extremely important to better understand the role of consumer directed genetic testing. Kudos to the groups that are sponsoring this important research. Testing is also available outside of a research protocol through the AAT Deficiency Testing Center. In contrast to 23andMe that provides results, but no other support, AAT testing is sponsored by AAT organizations that can provide support for newly diagnosed patients.

It should be noted that one can also measure the level of alpha 1 antitrypsin activity in the blood stream, obviating the need for a genetic test. So, if you’re interested in being tested for AAT deficiency, probably better to use one of these services than 23andMe. However, if you have been identified as carrying a mutation through the 23andMe testing, contact one of the advocacy organizations for more information. It could save your life!


Hogarth DK, Rachelefsky G. Screening and familial testing of patients for alpha 1-antitrypsin deficiency. Chest. 2008 Apr;133(4):981-8

Strange, C, Moseley, MA, Jones, Y, et al Genetic testing of minors for α1-antitrypsin deficiency. Arch Pediatr Adolesc Med 2006;160,531-534

Gitter AC, Jones Y, Schwartz L, et al. Confidential home α1-antitrypsin testing: specialty center support for rare diseases. Presented at: the American Thoracic Society Annual Meeting; May 18–23, 2007; San Francisco, CA; poster A988

Strange, C, Dickson, R, Carter, C, et al Genetic testing for alpha1-antitrypsin deficiency. Genet Med 2004;6,204-210


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  2. A good resource for information on alpha-1 is the
    http:\\ and another one that was also mentioned here is the foundation at
    http:\\ Both great reasources and links to people who care about any one dealing with anything alpha-1 related. I know... I have alpha-1 deficiency.

  3. A resource available to patients, family members, and health professionals is the Alpha-1 Association Genetic Counseling Program. It provides confidential, toll-free genetic counseling for Alpha-1. You can speak with a certified genetic counselor that specializes in Alpha-1 by calling 1-800-785-3177.

  4. I got tested after becoming sick with pneumonia in February 2013. It was taking a while to get better. After a blood test in Early May 2013 I was told I have alpha-1 (mz) gene. I had no idea what he meant. I started doing my own research and discovered this is a very scary thing to have. It is July 2013, I am still having shortness of breath and fatigue a few times a week. I have to be referred to a specialist to help out. I'm 45 years old. I can't believe I went from being very outgoing outdoors person to some one who has to be limited on how much I do on a daily basis.

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  8. I am a carrier also (MZ) and I have fatty liver (had MRI due to sporadic nausea/pain). I am currently waiting on labs from a liver Dr in Plano, but I'm wondering if having a fatty liver could exacerbate the abnormal Z allele getting "clogged" and accumulating in the liver, eventually causing scarring?

    1. This is a really smart question that we can't answer here. We can't give clinical advice. If your liver Dr. does not know about Alpha1, find one that does.