Kyle Hogarth, MD, professor of medicine and medical director of the Pulmonary Rehabilitation Program and director of the Alpha-1 Antitrypsin Deficiency Clinical Resource Center at University of Chicago Medicine. 

Kyle Hogarth, MD

my entire life, I was naturally drawn toward pulmonology as a specialty when I decided to become a doctor.

This fate was sealed during my medical school interviews, when I sat in on one specific lecture. I was enthralled by how the speaker explained the complex physiology of the lungs with such elegant simplicity. Later, when I learned about alpha-1 antitrypsin deficiency (alpha-1), it felt like the ultimate intersection of my fascination with genetics and my personal connection to pulmonary medicine.

Fast forward to when I was out of medical school, and early in my career as a pulmonologist, a colleague challenged me. His question was simple and straightforward: “What do you know about Alpha-1?”

I gave him the standard, technical answer: “Alpha-1 is a genetic condition that increases a person’s risk of obstructive lung disease and sometimes liver disease. Although it is thought to be a relatively common genetic condition, it is frequently underdiagnosed.”

He recognized that I was giving a textbook response and pushed back, asking, “Have you actually read the guidelines?” I had not.

That brief, albeit somewhat humbling, conversation shifted something in me. I went back, read the guidelines, and began changing how I approached my patients.

That experience proved that a good challenge could change the course of a career. Now, my goal is to pass that challenge onto my peers.

The truth is, there are far too many people living with obstructive lung disease, including COPD, emphysema, and chronic obstructive asthma, who have never been tested for Alpha-1. To my fellow physicians, I urge you to start thinking “inside the box”—specifically, by checking a box in your patients’ EMR to include Alpha-1 testing. This simple action can make a world of difference in uncovering this under-recognized disorder.

There is no secret, special clinical gift to diagnosing Alpha-1. It simply requires following the guidelines to ensure your diagnostic workup includes Alpha-1 testing. I continue to be astounded by the number of times this simple box is skipped over.

Guidelines call for Alpha-1 testing in all patients with COPD, emphysema, and chronic obstructive asthma

Common but frequently underdiagnosed genetic condition

Classic profile (< 45 years old, severe emphysema) misses many cases

Documented across all races and ethnicities, not just northern European descent

Lost lung function cannot be recovered, making early testing critical

As physicians, it can sometimes be easy to fall into clinical complacency. We tell ourselves, “Alpha-1 is too rare to warrant a test.” But the guidelines are clear: every patient diagnosed with COPD, emphysema, and chronic obstructed asthma should be tested for Alpha-1.

Consider the steps we already take to come to a diagnosis of an obstructive lung disease. Adding Alpha-1 testing is not a huge lift; it is simply completing the workup we started. And Alpha-1 testing is widely available, including sponsored testing at no charge. We are already drawing blood to check other labs as part of this workup. Why not check 1 more box and include Alpha-1 testing?

One major roadblock to diagnosing Alpha-1 is the archetype of the patient. The classical 

 described in the literature is young, less than 45 years old, with severe emphysema.

While those patients do exist, Alpha-1 can have varied presentations. If you only test patients who fit that narrow profile, you will miss others with the condition.

We also must dispel the notion that we should only test patients we intend to treat. Some physicians may think, “Why test if they aren’t severe enough to treat with augmentation therapy?”

The answer lies in preventative care and lifestyle modifications. When patients learn they carry a genetic risk factor for lung disease, they often make decisions to proactively protect their lungs, such as avoiding environmental pollution or quitting smoking.

Additionally, we must also disregard the old-school myth that Alpha-1 affects mainly people with northern European descent.

 While historically described in those populations, Alpha-1 has been documented across every race and ethnicity. If your patient has obstructive lung disease, they need to be tested, regardless of race or background.

We must find these patients early because of a simple reality: loss of lung function is irreversible.

We all lose lung function as we get older—it’s a natural part of the aging process.

But in Alpha-1 patients, the loss is potentially accelerated.

Let’s look closer at the cellular level. The primary role of the protein alpha-1 antitrypsin (AAT) is to inhibit neutrophil elastase, an enzyme that degrades elastin in the lung’s alveolar walls.

When a patient has Alpha-1, this enzyme goes unchecked. Think of it as a town overrun by fires with not enough firefighters to put out the flames.

When I diagnose patients who have dramatically declined lung function, I can support them, but I cannot give them back what they lost. We need to shift the timeline. We must find these patients 

while they still have most of their lung function intact

so we can step in and prevent more flames from forming for as long as possible.

Our therapeutic goal for Alpha-1 patients with obstructive lung disease is to help protect the lungs.

For decades, weekly augmentation therapy, intended to raise AAT levels in the lungs and bloodstream, has been the standard of care for these patients.

Historically, we have aimed for a putative target of maintaining serum AAT levels above a threshold of 11 µM, a benchmark long thought to be the minimal serum protein level before the risk of lung disease sets in.

 However, this threshold has been increasingly questioned and is potentially due for a reevaluation.

 Other research has shown that risk of potential lung damage may increase when patients’ AAT serum levels fall below the range of approximately 20–53 µM, with the degree of that risk dependent on other factors like genotype or exposure.

I began with a story of being challenged earlier in my career, so it is only fitting to close with a challenge of my own.

I recently gave a talk on Alpha-1, and a fellow physician pushed back on the lack of data regarding therapy in the space, explaining he doesn’t often test patients for Alpha-1 because of this lack of data. My response was straightforward: “We’re never going to get the data you’re looking for if doctors aren’t testing.”

I worried I had been too blunt, but it turns out the message hit its mark. He has started routinely testing his patients for Alpha-1. For me, that is a mission accomplished.

If we want better data, better trials, and better treatments, we have to start by checking the box. Test your patients for Alpha-1.

Hogarth was compensated by Sanofi for his time on this article.

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Articles

Alpha-1 antitrypsin deficiency remains underrecognized in obstructive lung disease despite clear guideline recommendations for universal testing in COPD, emphysema, and chronic obstructive asthma. Routine EMR-enabled testing can overcome clinical inertia, broaden detection beyond the “young severe emphysema” stereotype, and address misconceptions about treatment candidacy and ancestry. Early identification matters because alveolar destruction from unopposed neutrophil elastase is irreversible and may be accelerated. Augmentation therapy remains foundational, while the traditional 11 µM protective threshold is increasingly debated.

Kyle Hogarth, MD, urges physicians to complete Alpha-1 testing during every COPD or asthma workup, warning that skipped tests delay diagnosis.