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Expert guidance in alpha 1 antitrypsin deficiency
Expert Guidance in Alpha-1 Antitrypsin Deficiency: Why Early Detection and Multidisciplinary Management Are Key

Released: May 09, 2025

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Listen in as Paula Henao, MD; Rohit Loomba, MD, MHSc; Cheryl Pirozzi, MD, MS; and Corinne Young, NP, FCCP, discuss their screening and monitoring strategies for patients with alpha-1 antitrypsin deficiency, including:

  • Why early detection is key for improving patient outcomes
  • How to monitor through use of noninvasive imaging and biopsy per guideline recommendations
  • How to coordinate patient care to provide much-needed multidisciplinary care
  • What therapies in the pipeline could transform the treatment landscape for this genetic disease

Introduction

Joshua Schechtel (CCO): Hello, and welcome to the Clinical Care Options Medical Specialties podcast. I am your host, Joshua Schechtel. Today's episode features a conversation with four experts in alpha-1 antitrypsin deficiency.

Gastroenterologist Dr. Rohit Loomba from UC San Diego, allergist Dr. Maria Henao from Penn State University, pulmonologist Dr. Cheryl Pirozzi from the University of Utah, and nurse practitioner Corinne Young from Colorado Springs Pulmonary Consultants, they are talking about how we can better diagnose and manage patients with alpha-1 antitrypsin deficiency. For more information on our speakers, along with a link to more resources, please visit the show notes for this episode.

Now let us get started and hear what the experts have to say about this important topic.

Dr. Rohit Loomba (University of California, San Diego): At UCSD, what we do, and this is typically what we would expect, any patient who comes with elevated ALT and AST, that is typically one of the reasons why somebody would get referred to our clinic, and usually it has been elevated over at least a six-month time period. That would be a patient that we would at UCSD evaluate for alpha-1 antitrypsin-related liver disease as an etiology for elevated ALT and AST. Now, of course, people who do not do that probably think about that it is a rare disease, so probably start with things that are much more common, and the common things would be thinking about whether somebody has viral hepatitis, hepatitis B, hepatitis C, autoimmune liver disease, and looking for ANA, as well as iron overload, looking for ferritin, and then thinking about fatty liver disease, whether it is due to alcohol or related to metabolic syndrome or obesity-associated fatty liver disease.

I think within that spectrum, the reason why we do it is because we do not want to be missing out on diseases that our patients may have because we are a tertiary care center. So that would be definitely one group of patients that we would do. I think it would be totally reasonable if somebody did in a sequential manner that if viral hepatitis was negative, then this could be the second set of tests if that is how they want to do it.

The other patient population where we have a high likelihood of testing for alpha-1 antitrypsin-related liver disease is somebody who already has a diagnosis from a pulmonary colleague for alpha-1 antitrypsin-related lung disease. So they may get referred. Now they already have a disease diagnosis.

Typically I will still, because many times they have been followed for many years with pulmonologists, they may not have a record of exactly what their genotype is or their phenotype is. So when they come to my clinic, I order levels, alpha-1 antitrypsin levels, I order a phenotype, and if genotype is available, I order a genotype. This way we are able to establish the diagnosis whether it has ZZ disease or MZ or another pattern. And this way we can inform them about their risk for liver disease.

Another group of patients who might come is somebody with COPD and emphysema as past medical history, and they have either elevated ALT or fatty liver or ultrasound or any other reason they might be seeing me. If they have a history of lung disease and particularly emphysema, I am extremely likely to be doing testing for alpha-1 antitrypsin levels and then phenotype or genotype.

I will stop here and see what my pulmonary and allergy colleagues do.

Dr. Cheryl Pirozzi (University of Utah): My impression is that the gap in diagnosis probably comes more on the pulmonary side. In my opinion, at least at our institution, I feel like the hepatologists are very consistent about screening everybody with unexplained liver disease for alpha-1. However, the guidelines call for screening in anyone with COPD, anyone with poorly controlled asthma, which are very common conditions.

And so I think among primary care providers or even pulmonologists and allergists, I think a lot of times those patients are not screened unless they have very classic alpha-1 findings like out-of-proportion emphysema, they are younger than expected, they have lower lung pan-asthma or emphysema. However, the reality is that it can look like typical COPD. And so I think a lot of times screening is not done when it should be.

Dr. Paula Henao (Penn State Hershey Medical Center): I will quickly echo Dr. Pirozzi and Dr. Loomba. Really, as Dr. Pirozzi mentioned, most of the patients with COPD are not screened. One study showed only 5% of patients with COPD are screened for alpha-1 antitrypsin deficiency, even though the guidelines really show that all patients with COPD or emphysema should be screened in addition with those with asthma and irreversible airflow obstruction, certainly unexplained liver disease, necrotizing panniculitis, unexplained bronchiectasis, or a first-degree relative with alpha-1 antitrypsin deficiency.

From my perspective, the biggest issue with alpha-1 antitrypsin deficiency has been our inability to really screen people appropriately. And when I talk to colleagues in other fields like primary care, we really do not have a great understanding of when screening should happen. And it seems like, oh, I am not going to screen every COPD-er. That seems unreasonable, even though there is free screening by the Alpha-1 Foundation. The studies from the Alpha-1 Foundation showed that their free screening kits were capturing abnormal alleles in 14.6% of the patients screened, which is they are capturing a huge volume of problematic alleles in the patient's screen, so we are clearly not screening enough.

Corinne Young (Association of Pulmonary Advanced Practice Providers): You had mentioned specifically about GI, about liver screening, specifically. And being in pulmonary, I am not aware of if there are GI guidelines specific to that outside of abnormal LFTs, but if it is in their specific guidelines, I am unaware of that. However, anybody that comes to us that is being evaluated for alpha-1, we are doing liver ultrasounds and LFTs, making sure they are getting their hepatitis vaccines, their titers are good, and then also, if they have not already been referred to hepatology or GI.

Dr. Loomba: One thing about liver disease evaluation, how often are you doing a FibroScan or a FIB-4 assessment in your patients with alpha-1 antitrypsin, or the hepatologist at your institutions or in your area are doing it? Because that is something that would also be important. Once we detect that somebody is, then we would want to see if they have fibrosis or not.

Many patients do not want a biopsy, so some sort of a non-invasive assessment is reasonable. And so, we are typically looking at their labs, the ALT/AST platelets, and then doing a FibroScan assessment or a MR elastography that is available.

Dr. Henao: So I get GGT, LFTs, and INR, usually every six months, and also an ultrasound. I must admit, I want to get it every six months, but a lot of times in practice, patients do not want to go to get an ultrasound every six months, so I let them slide a lot of times and let them go for a year if they have had normal ultrasounds. I know the guidelines are a little bit iffy every six months versus a year, especially in those patients that have been doing well.

Dr. Pirozzi: My practice has been to screen annually with labs, the same labs you all have mentioned, and get an ultrasound. I refer to hepatology if there is any abnormality, and then they usually coordinate the elastography test.

Dr. Loomba: One thing I would say that typically the ultrasound and then potentially AFP is needed in the setting of cirrhosis due to alpha-1 antitrypsin-related liver disease. You could do an ultrasound baseline, I agree, you do not need every six months or every year if the patient is non-cirrhotic. However, I think if you do not know that, then I think it may be reasonable, assuming that they may have more advanced disease than doing less for them.

Because with alpha-1 antitrypsin-related liver disease, particularly those who are ZZ, there is a high risk for developing liver cancer, particularly if they were cirrhotic. Once they develop cirrhosis, then our recommendation is for anybody with cirrhosis to screen with ultrasound plus AFP, alpha-fetoprotein, a blood test every six months. Suppose you had somebody with alpha-1 antitrypsin-related liver disease, and then you referred the patient to me. I did a FibroScan, and FibroScan was 7 KPa, and that patient has a pretty low likelihood of having cirrhosis. So that patient does not need ultrasounds periodically. You could repeat a FibroScan, say, every 1‑3 years in that patient, because they have a mild disease. And if there is progression, and when the liver stiffness reaches the cirrhosis range, then you can think about doing annual or every six months ultrasound and AFP.

Dr. Pirozzi: I monitor lung function. I do annual, generally annual, PFTs. If someone is clinically unstable, I might check more frequently at first, but then usually annual lung function tests.

In terms of practicality, I think if you have someone who has very mild disease or no lung disease and has totally normal PFTs for multiple years in a row, I will often then spread it out a bit more. However, the guidelines say annual.

Dr. Loomba: Yes. For us, from a liver disease perspective, I think first is a diagnosis, establishment of whether they have fibrotic disease or not. Typically, we would start with a noninvasive assessment.

So you can start with a FIB-4. The FIB-4 is below 1 or above 1 or below 1.3 or above 1.3. It gives you a likelihood of advanced fibrosis. So if it is below 1.3, low likelihood of advanced fibrosis. We will also do a FibroScan or MR elastography. If the FibroScan reading is below 7 or 8 KPa, then they do not have fibrotic disease or low risk of fibrotic disease. The FibroScan is 20 KPa or higher, we think about cirrhosis.

So somewhere in between, you have got various stages of fibrosis. So depending on where their liver stiffness might be, we will determine the potential frequency for their repeat FibroScan assessment. You could vary between 1-3 years for a repeat FibroScan assessment.

Liver-related enzymes, if they are abnormal, you could probably assess them every six months or so. And at some point, probably consider doing a liver biopsy. One thing we have seen in patients with alpha-1 antitrypsin-related liver disease is sometimes their ALT and AST may be just above or just below the upper limit of normal. And most people may not recognize that. So an ALT of, say, 35 and AST of 30 is abnormal, but most labs would say AST upper limit of normal might be 35, somewhere like 40. So typically a normal AST is around 20.

And so you can see that even within normal limits for patients' ALT and AST, they can harbor liver disease that is occult and progressing and nobody knows about it. And then it also gives an opportunity to look at our success of lifestyle interventions during those visits as well. However, that is the monitoring.

And, you know, as Paula and Cheryl mentioned, once you develop cirrhosis, then we want to do a monitoring for hepatocellular carcinoma. That is typically done with ultrasound plus alpha-fetoprotein or blood tests every six months or so. And then we would watch them for liver disease decompensation. So they might get esophageal varices screening with an upper endoscopy.

And if they develop ascites, so the ultrasound every six months that is happening helps with assessing for ascites, which is water developing in the abdomen due to portal hypertension. Then some patients with more advanced disease can be at risk for hepatic encephalopathy. However, that is very, very rare when somebody has cirrhosis and decompensation. And we monitor. Those patients will be in a liver clinic and being monitored by a hepatologist.

Noninvasive assessment is helpful, it has good, but it is all presumptive. So we assume that because they are ZZ that the liver enzyme elevation is absolutely related to alpha-1 antitrypsin deficiency. And when we do the biopsy, we confirm that diagnosis. At the same time, we are going to rule out other causes for liver disease.

So we can also determine concomitant liver disease. So if this patient also had fatty liver disease, whether it is due to alcohol or whether it is due to metabolic dysfunction-associated steatohepatitis or MASH, your biopsy will confirm that. The pattern of injury that we see with alpha-1 antitrypsin-related liver disease is very different than the pattern that we see with fatty liver disease.

So we can distinguish as to what is the driving force for this patient's liver problem. And so biopsy can be helpful. And biopsy is also helpful in excluding other causes. For example, is there iron overload? And so we can assess for that. Is there autoimmune liver disease? We can assess for that. So it can be helpful either in ruling out, confirming the disease, and finding concomitant liver problems that could be very common.

Dr. Pirozzi: I think education is huge. I, personally, work a lot with trainees of all different levels, medical students and residents and fellows. So we do a lot of training for those groups.

And then I think educational programs for primary care providers, pulmonary providers, allergists, and hepatologists too. I think just education, even within my specialty, most people do not know or remember that you are supposed to screen everybody with COPD for alpha-1.

Corinne Young: There are so many pop-ups that happen, you just want to get through your notes or something like that. It may help some people. It may not help others.

I know with lung cancer screening, we have a pulmonary nodule clinic as well. One thing that has helped our community-based practices, our primary care docs, is that there will be a little blurb at the end of the report noting that there are these small incidental nodules and to consider the Fleischner guidelines and recommendations for screening based on the nodule size and the patient's risk. So they note that in the results.

So it may be, I do not know, beneficial when, if there is a primary care with forward-thinking to do alpha-1 screening, when they get the test results, could there be a little blurb at the bottom to consideration for LFTs, liver ultrasound, lung function testing, referral to a CRC or pulmonologist or GI specialist, something along those lines. It was almost like a checkbox for them in the results section.

Dr. Henao: The Alpha-1 Foundation has done a really tremendous job in terms of trying to increase screening, and they have done a great job in terms of providing, I do not know if you guys use it, we do the free screening from the Alpha-1 Foundation routinely in our practice. Being able to have that more readily available for primary care doctors would be really helpful because I think screening, if it has a costly test, like if you are getting levels, that is very expensive for patients, and so that might not be reasonable, but the free screening I think is a great thing. I do think that potentially doing more research on who to screen is critical.

So right now I think primary care doctors see these current guidelines, and they do not buy it, to be honest. I have had conversations with a lot of primary care doctors saying, I am not going to screen every patient with COPD, that is nonsensical. So figuring out if there is some models of who are the patients that are going to be the highest yield for screening, that would be very effective, I think, in terms of getting more buy-in from other physicians for wider screening practices.

Dr. Loomba: Particularly, I think it should be clinic-specific so we can understand the yield. So for example, in your clinic setting, so people could take a look at what the yield rate would be if you were to screen 100 patients, you will find two or five. And then the same thing, Cheryl, in your clinic with COPD or with asthma, I think those would be very helpful.

And Corinne, you also mentioned that you have other pulmonary etiologies and it could also be different, those coming to see you at the university or the community-based sites because the prevalence might be different. And regionally, of course, there will be enrichment at more tertiary care centers. And then we can certainly increase the yield by adding additional risk factors.

Say family history of cirrhosis would be something because it is an important genetic cause for cirrhosis. So that could be something, particularly if somebody had lung disease and liver disease in the family. So I think family history is an important component.

And then if you have your brother, sister, mother, father with alpha-1, that you should be tested as another area. And I think that also can be assessed.

Dr. Pirozzi: When I see a new patient with alpha-1, I will talk about the genetics of it and how it affects family members and then offer screening for family members, usually to the Alpha-1 Foundation because that is an easy send out, but at least have that education. I think even if you are seeing someone, I often will see someone who is heterozygous, a carrier, it has not really clinically a severe deficiency. However, by identifying this one person, you then identify a whole family, and there are sometimes people with more severe deficiency and more significant clinical disease.

Dr. Henao: For us, it has an in-house conversation. We do not really use genetic counseling for alpha-1 antitrypsin.

Dr. Loomba: Resources are limited. So we tend to focus on if they have liver disease and how much they have, and if there is a family member who may have an occult liver disease. So really the focus is that.

Genetic counseling in terms of what their long-term lifetime risk of developing cirrhosis might be. The other reason is that you have time in the sense that if you can catch it early, it has a slowly progressive disease, so you can by lifestyle changes really augment the natural history of liver disease progression.

Corinne Young: We use services like pulmonary rehab, you know, for the patients that have pulmonary manifestations, they get pulmonary rehab referrals, the co-specialty if we think there is some common liver disease, they go to GI, but I think for the most part, it stays in-house.

Dr. Pirozzi: We have a medical bariatrics program that either I or often the hepatologists will refer people to who have fatty liver disease, and that could be really helpful.

Dr. Loomba: I think the risk of liver disease progression by having another liver disease is significantly higher with alpha-1 antitrypsin, particularly in ZZ or even MZ. So I think what patients do not know is that the damage they can have to their liver with obesity, or type 2 diabetes, or excessive drinking is much more than an average person. And I think that is the sort of knowledge if you provide that to the patient, the likelihood of them making that change in their lifestyle is much higher.

And so to me, I think that is really the most important thing, that reversing, that discussion that if you did not have alpha-1 antitrypsin-related deficiency, then your risk would have been an average risk. Now that you have it, your risk is now two to three times higher for developing cirrhosis. And if you can avoid or abstain from alcohol, you would reduce your risk significantly.

And if you can maintain a normal body weight, then you would reduce your risk significantly for liver disease progression. I think that conversation helps with the patient. However, the thing is that by the time they come to us, it is not like that discussion is happening at age 20 or 30. Majority of the patients that we will diagnose who have advanced disease are in their 40s, 50s, and 60s.

Joshua Schechtel: Are there other departments or other specialties that also play a significant role?

Corinne Young: Maybe respiratory therapy, because they are getting routine PFTs. They may spend some time, depending on the involvement with respiratory therapy education. We have two respiratory therapists in our practice. They do a lot of education with patients, do their walk testing, do their oxygen qualifications and their lung function, inhaler technique, education, things like that.

Dr. Henao: In terms of screening, though it is not part of the interdisciplinary care, I think radiologists being involved in the conversation of screening, if they see certain lung abnormalities, certain liver abnormalities, they can write a note, "Consider testing for alpha-1," so that could increase screening practices. I think overall, I have had good experiences with interdisciplinary communication as long as it is within the same medical record system.

Sometimes that is a big barrier. If their gastroenterologist is outside, sometimes getting consistent records, getting good flow of communication, we do not have easy ways of messaging each other if something goes wrong or if something else needs to be followed up. That is a big barrier from my standpoint. When they are your colleagues, I think things are a little bit easier and smooth sailing from my perspective.

I assume the care of the alpha-1 patient, and within our field, we are really great at coordination of care with patients that need multidisciplinary care. I assume so also with pulmonology, but we have our patients with primary immunodeficiency, and so we have to coordinate a lot with GI and other subspecialties. This is just a part of how we handle care.

In our institution, we are alpha-1 center in the allergy division rather than pulmonology, so it works a little differently, but we do a really great job coordinating care. We do all the orders for augmentation therapy, etc., coordinate with pharmacy and then coordinate with GI. If something else needs to be done, we directly message GI, so we are really the main person to coordinate care as opposed to the primary care doctor in that setting.

Corinne Young: I am a private practice, community-based practice, so we are not associated with the healthcare system, and we end up doing it all, but we are also the CRC for alpha-1. There is only three in Colorado and we are hundreds and hundreds of miles apart, so most things filter into us because of patients going to the website. They did back when they could do it on 23andMe and they would find out they were a carrier or they had abnormal alleles, they would come find us through the alpha-1 website or primary care. We have done a lot of outreach with our primary care practices about alpha-1 education, screening, and then sending them to us, but then we end up coordinating all the other ancillary care.

Dr. Pirozzi: Maybe one unique thing about our setting is that we are the only CRC in a four-state area, and so I see patients that are referred from very far away, and the Alpha-1 Foundation is helpful for that as well. However, as a result, I will see people who live, I do not know, as much as six or seven hours away. I am not going to be able to see them very frequently, so I will see them maybe annually, and then in between, the primary care physician will be the one to be managing lung disease, acute exacerbations, things like that. And so in those situations, I do try to communicate with the primary care provider.

And then I think regarding kind of the hepatology-pulmonary collaboration, that I think works well within our institution. So someone may be referred first to me because of lung disease, and then if I detect anything abnormal with the liver, I will refer to my colleagues in hepatology and we can talk easily. And then vice versa, if someone is referred for liver disease, they will refer to me to assess for lung disease.

It is a little challenging. I have a great clinic team who requests records and imaging from outside hospitals, so that is very helpful. However, then when I want to communicate with them, I will usually just try to call and get a call back, and then we talk.

Joshua Schechtel: The therapies that are kind of coming down the road in the next two to five years, what kind of impact that is going to have, not just on your patients, but on how you practice?

Corinne Young: When we see our patients, again, because we are a CRC, we try to talk to them about what is going on in the pipeline and what things may be coming and that type of thing. And these patients are pretty well educated. A lot of them get involved with the Alpha-1 Foundation, so they also are getting information.

So I anticipate we are going to be seeing our established, stable, augmented patients more frequently because when they hear something is approved, I assume they are going to want to come in and talk about options, especially a lot of patients are very excited about the possibility of the nebulized therapy versus getting the infusions. Financially, I am excited about the recombinant options. That might be something where we do not have to be so reliant on plasma donors and cost and reconstitution and all those things that kind of go with that. Is that going to look different with recombinant therapies?

And then CRISPR, I mean, oh my gosh, how exciting is that information? And then where do we even send them, and who is going to manage that? And so there is a lot more unknown, I think, with that. However, I know patients are going to have lots of questions about it.

So I do anticipate volume visits are going to increase because they are going to want to have these discussions with us about do we need to change their therapies? Could we change the therapies? Are there other options for them than what they are currently doing?

Dr. Pirozzi: We have not been involved in clinical trials for any of the gene therapy as opposed to some of the other therapies. So I think I am less familiar with how that will look in practice.

Dr. Henao: I think overall, this is such an exciting time for alpha-1, right? Just as Corinne pointed out, we have all the longer-acting forms of augmentation therapy, the inhaled augmentation therapy, potentially a subcutaneous or the recombinant. And then we have CRISPR technology coming that could really change the way we manage disease and be almost curative.

And then we have for liver disease, we have like RNA technologies and antisense oligonucleotides and small molecule correctors. So all these different technologies in the pipelines that may really change the landscape in a big way for alpha-1 antitrypsin deficiency. And that is incredibly exciting.

At the same time, we also need to consider going back to the basics. I mean, that is so exciting for all the patients that have been diagnosed. I keep on going back to we may have about 100,000 patients in the U.S., and maybe about 90,000 of them have not been diagnosed. So all of these fantastic new technologies that we may have available for our patients, including potentially curative technologies, will be almost null if only 10% of the patients are diagnosed. We really need to capture these patients with novel screening therapies. And then also, you know, going back to basics, we talked about maybe things related to liver disease. We have not really touched on, smoking cessation, some of the basics, lifestyle changes that can really be life-altering for alpha-1 in addition to these super cool new therapies.

Dr. Pirozzi: I think it has a very exciting time, and I definitely expect to see the landscape of therapies change in the next ten years. However, I agree with you. I mean, you know, more important than these potentially is just smoking cessation, just, you know, avoiding the exposures that lead to lung disease in the first place.

I guess a little different with the liver disease. Some of these things will have the ability to correct both liver and lung disease. But just being able to diagnose, do a better job of identifying people who have alpha-1 antitrypsin deficiency and then just addressing the very basic exposure avoidance strategies, I think is still really key.

Just reemphasizing the guidelines for diagnosis. Everyone with COPD, everyone with asthma, with fixed airflow obstruction, everyone with bronchiectasis, everyone with liver disease. And then, you know, some of these rarer things too, panniculitis and vasculitis.

However, I mean, just the common diseases we are not screening like we should be. And a lot of that happens on the primary care side.

Dr. Henao: I completely echo with Dr. Pirozzi. That is the biggest barrier. Even the big diseases, there is a lot of hesitance to screen widely, even though there is free testing. I do not think there is enough knowledge. So from an education standpoint, I think there is a lot of education that these free tests are available, that it has only a cheek swab, that it is anonymous, that it will not necessarily go into the medical record, because sometimes that is a fear of repercussions from the medical record.

And then, you know, what we discussed, vaccinations and smoking cessation is going to be number one, two, three, four in terms of management of alpha-1.

Dr. Pirozzi: Yes, I think there may be a role for a clinical decision support tool system, things like that. However, it has just hard to figure out how to do it without being another notification that someone clicks away.

Joshua Schechtel: Thank you to our faculty, and many thanks to you, our listeners, for joining us. As a reminder, to view additional resources, please click the link in the show notes, and be sure to check back regularly for more episodes on important medical specialist topics.