Where Are They? Patients with Alpha-1 Antitrypsin Deficiency

Podcast Transcript

Raed Dweik, MD:

Hello, and welcome to the Respiratory Exchange podcast. I'm your host, Raed Dweik, chairman of the Respiratory Institute at Cleveland Clinic. This podcast is intended for healthcare providers and covers topics related to respiratory health and disease. My colleagues and I will be interviewing experts about timeless and timely topics in the areas of pulmonary, critical care, allergy, sleep and infectious disease. I hope you enjoy today's episode.

Hello, and welcome to this episode of the Respiratory Exchange podcast. I'm your host, Raed Dweik, the Chairman of the Respiratory Institute at the Cleveland Clinic. And my guest today is Jamie Stoller, MD. Dr. Stoller is the Chairman of the Education Institute at the Cleveland Clinic and he's a nationally and internationally recognized expert in Alpha-1 antitrypsin deficiency, which is the topic of our podcast today. Jamie, welcome.

Jamie Stoller, MD:

Well, thank you, Raed. I'm delighted to be here.

Raed Dweik, MD:

So let's start with the basics. What is alpha-1 antitrypsin deficiency gene?

Jamie Stoller, MD:

So alpha-1 antitrypsin deficiency, Raed, is a genetic condition, it's inherited and it gives rise to a risk for several conditions - lung disease, particularly emphysema or COPD, and liver disease. As we'll discuss, the pathophysiology is very interesting and the pathogenesis of the liver disease is actually different than that in the lung, but it can give rise to both, either in the same individual or in different individuals. There's also a predisposition to an unusual skin condition, an inflammatory skin condition called panniculitis. And lastly, a fascinating association with vasculitis, with C-ANCA vasculitis. So genetic condition predisposes to four important clinical features, as I've mentioned.

Raed Dweik, MD:

Wow. It looks like affects multiple organ systems. How common is it?

Jamie Stoller, MD:

You know, it's, it's pretty common actually. There are population-based studies based in Sweden and in this country that suggests that the prevalence in the United States is about one in 3,500. A large study with one of the direct consumer genetic companies, in which we participated, sampled three million users of that service and demonstrated a prevalence of about one in 3,800, which quite agrees with the prior population-based screening studies. When one looks at the population of the United States, this gives rise to an estimate of about 100,000 Americans with severe deficiency of alpha-1, the so called PiZZ type, that I'm sure we'll be discussing.

Raed Dweik, MD:

So that's a lot of people, but we don't see that many in clinic on a regular basis. Where are they?

Jamie Stoller, MD:

Well, that's a great question. And one of the signature features of this, which has been the subject of much research and many efforts to enhance diagnosis, is that this is under-recognized, severely under-recognized. So that, for example, of the 100,000 Americans, we estimate that fewer than 12,000 are clinically recognized, leaving the majority of affected individuals and, of course, their family members, because again, this is a genetic disease, unrecognized in our midst. Now, in fairness, some of those patients go through life unaffected, particularly if they don't smoke. But there are many patients, we see them all the time in our clinic, that are afflicted by chronic obstructive pulmonary disease or liver disease, that actually have alpha-1 as a predisposing condition but are unrecognized as being so.

Raed Dweik, MD:

So why do you think there's this delay in diagnosis or under recognition in general? Why do you think that is?

Jamie Stoller, MD:

Well, I think there are several reasons. Of course, all of the guidelines, and there are now 15 international guidelines on alpha-1 that we've reviewed, all of them are concordant in suggesting that every patient with fixed airflow obstruction on pulmonary function tests be tested once in their lifetime with, in the ATS guidelines, a serum level for alpha-1 and a genotype. And yet we know that doctors are generally relatively refractory to guideline implementation. We see this in many conditions, you know, low stretch ventilation and ARDS, even though ARDS net was published more than two decades ago, we still see incomplete compliance with guideline-based practice. So that's one reason.

The other is there is a sense of therapeutic nihilism by some folks, the idea that there is no effective therapy. And, therefore, why burden a patient with a psychologic burden of a genetic disease? Now, that's not true because there are effective therapies. And importantly, we are on the doorstep of a number of really very, very innovative treatments that will likely come into the armamentarium in our lifetimes. Those are the major reasons.

Raed Dweik, MD:

These are big, big reasons. I can I can understand how there's under-recognition. So what's the underlying pathogenesis of alpha-1 antitrypsin deficiency? How does it happen?

Jamie Stoller, MD:

Ultimately, alpha-1 antitrypsin deficiency, of which there are more than 150 genotypes, the most common severe genotype is the so called ZZ type, which is a single amino acid substitution at position 342 on a 394 amino acid glycoprotein. And in the case of the Z protein, the 342nd amino acid is a lysine instead of a glutamic acid. That strategic substitution causes a conformational change in the molecule as it's synthesized in the hepatocyte. And that conformational change allows the Z protein, unlike the normal M protein, in which all 394 amino acids are normal, the Z protein when released from the ribosomes folds abnormally in a way that exposes one of its beta sites, and the beta loop invites an adjacent Z molecule to intercalate itself and polymerize within the hepatocyte.

So that Z type alpha-1 antitrypsin, which is the most, again, the most common deficient variant, 95 percent of clinical disease relates to ZZ individuals, in that case, the Z protein polymerizes in the hepatocyte. That polymerization precludes it secretion into the bloodstream, which causes a downstream deficiency in the bloodstream and therefore in the lung. So the pathogenesis really twofold. It's primarily hepatic inclusion disease, ZZ type, which predisposes the toxic so-called gain of function, the excess protein in the liver cell predisposes to liver disease. And the lung disease is said to be a toxic loss of function. Namely, there's too little in the bloodstream, therefore too little in the lung. And we know that alpha-1 importantly opposes neutrophil elastase, which is a proteolytic threat to the lung and which breaks down elastin, and therefore alveolar walls. So the emphysema is related to too little alpha-1 in the lung and the cirrhosis is related to too much alpha-1 in the liver.

Raed Dweik, MD:

Wow, what a fascinating paradox. It's really two sides of the same problem. So clinically, how does this manifest when patients present to us? What does it look like?

Jamie Stoller, MD:

Most commonly with COPD and its course. As you and all of our pulmonary colleagues know, this characteristically presents with shortness of breath, there's often a delay in even recognizing COPD, the importance of doing spirometry very early. And with the recognition of fixed airflow obstruction, post bronchodilator, fixed airflow obstruction on PFTs, that should, again, by guideline, indicate testing for alpha-1. So it presents with dyspnea. There are some patients who have bronchiectasis, and so they present with copious phlegm, episodes of haemoptysis. And occasionally this can present as liver disease proceeding the lung disease, although that's a relatively less common scenario. The prevalence of liver disease depends on the series but maybe as high as 40 percent in ZZ individuals. The prevalence of COPD is likely higher, particularly, again, if individuals smoke or work in dusty occupations, steel mills, firefighters, et cetera.

Raed Dweik, MD:

Thank you for explaining that. So what happens in the natural history of the disease? Do the patients progress, stabilize. What happens with them over time?

Jamie Stoller, MD:

It's characteristically a progressive disease. And we know this from the results of the National Heart Lung and Blood Institute registry, which was a study done in the 80s in which we at the Cleveland Clinic served as the coordinating center and engaged with 36 other centers around the United States and Canada, which as a group followed 1,129 individuals. And we characterized, over about seven to 10 years, the changes in FEV1 over these individuals, and identified the fact that in ex-smokers the rate of FEV1 decline in these individuals was 54 ml per year. Recognizing that the normal age, as you well know and our colleagues well know, the normal age related decline in men and women is roughly 19 to 22 ml per year from Framingham and other studies.

In never-smokers, that number may be as high as 67 ml per year. And in current smokers, thankfully, very few in the registry, only 8 percent, that number is 109 ml per year. So they lose lung function, on average, fivefold faster than normal. Recognizing that there are, of course, subsets of individuals who have deficiency of alpha-1, who thankfully never experience accelerated decline. That is likely a minority of the individuals, but I have seen them in my practice and I'm thankful when I see such individuals.

Raed Dweik, MD:

Wow, that's huge, the impact of smoking. So, see the combination, the deficient is like a two hit almost, like the deficiency and then the smoking on top of that. Do we have any explanation for those who do not get progressive disease or that's an area of research?

Jamie Stoller, MD:

It's an area of somewhat uncertainty. So collaborating with colleagues in Boston and with Dr. Silverman and others, we've looked for genetic modifiers and have found in genome-wide screening some genes that seem to be disproportionately represented in sibling pairs where there's discordant phenotypes. But truly, this is not well understood, what it is other than the avoidance of cigarette smoking, that protects some individuals and subjects other individuals to progressive airflow obstruction is, I would have to say, incompletely understood in 2022.

Raed Dweik, MD:

Yes, just to clarify that, so definitely smoking is a major enhancer of loss of lung function, but people can lose lung function even who don't smoke.

Jamie Stoller, MD:

Absolutely.

Raed Dweik, MD:

Because of the deficiency.

Jamie Stoller, MD:

Absolutely.

Raed Dweik, MD:

Yes. So it seems like it's under-recognized, as you mentioned earlier, so how does a practitioner, either pulmonary or maybe a general internist gets exposed to this, how do they make the diagnosis? How do they suspect and diagnose it?

Jamie Stoller, MD:

Well, the diagnosis is, thankfully, easy. It's a simple blood test. One would check for a serum level of alpha-1 antitrypsin in the bloodstream. Normal ranges in most labs are about 90 to 220 milligrams per deciliter. This is also sometimes expressed in micromolar, where the normal range is 20 to 53 micromolar. And ideally, in my view, one would also send a genotype, which is generally in labs done with PCR probes for the most frequently represented abnormal alleles. Which in our lab at the Cleveland Clinic is the Z allele, the S allele, the I allele, and the F allele, as in Frank.

Raed Dweik, MD:

A lot of alleles to remember, you know. But they're all tested for routinely, so the practitioner does not have to order these alleles, just to send for the genetic test and that's done routinely.

Jamie Stoller, MD:

Exactly. It is important to understand what the laboratory to which you send your specimens does, because there is some variation in laboratory practices with regard to which alleles are tested for, and in some cases, how the testing is done. Some laboratories will do isoelectric focusing looking for a band pattern as the protein migrates on a protein gradient from pH four to five, and looks for the banding patterns, which is a very subtle art. And again, many laboratories will do the PCR probes. And finally, when there is a discordance between the clinical phenotype and the serum level, let's say the patient has a low level of alpha-1 antitrypsin but no abnormal allele found, then there's a role for either Sanger or next generation sequencing, whole exome sequencing to look for unknown variants, currently unknown variants.

Raed Dweik, MD:

Yeah. So the key is to find a way that the clinical picture and the testing are concordant-one way or another, so that you know what you're doing. That's great advice. Then who do we test? Like, do we test everyone with COPD or are there any salient clinical features that will suggest that we test? Or what are your suggestions for the pulmonary practitioner around that?

Jamie Stoller, MD:

Well, in the end of the day, every patient with COPD should be tested. Now, when we read textbooks, we're used to thinking alpha-1 presenting in a young never-smoker with lower lobe emphysema as the classic clinical picture. And while those are characteristic features, I will tell you that if you depend on those clinical criteria to hone your testing, you will miss most of the patients. We know as part of this under-recognition, for example, that patients we studied this years ago and it regrettably remains true today, that these patients will spend about six to eight years from the initial onset of dyspnea to initial recognition of alpha-1, and will, in some series, see as many as 12 physicians before the diagnosis is initially made. I see this in my practice quite commonly. And so, there really is an impetus to have a low threshold to test. And again, guidelines suggest that every patient with fixed airflow obstruction on PFDs should undergo testing once in their lifetime.

Raed Dweik, MD:

I mean, from the testing sample is a simple blood test, so that makes it easy. It's not like a complicated test, it's not a biopsy or anything, so I think that should make it easy to do. But what about the expense, is this covered by most insurances?

Jamie Stoller, MD:

It is and in addition to that, many groups, obviously the companies that produce drug for alpha-1 as well as the Alpha-1 Foundation, offer free testing. So the Alpha-1 Foundation offers what they call the alpha coded testing trial, where one would go online, sign up, receive a dried blood spot test kit and a lancet, prick the finger, put a little bit of a blood spot on a card and send it in. This is analyzed by Dr. Mark Brantly's lab at the University of Florida, which is subsidized by the Foundation. And the patient would receive, confidentially at home and at no cost, their serum level and genotype. So, insurance covers most testing, but if one is disinclined to do that, one can avail oneself of these alternative testing strategies. And there really is no financial disincentive in that context.

Raed Dweik, MD:

That's a great service. And if I understood correctly from you, it doesn't even need a physician order, the patient can just request that and do it on their own.

Jamie Stoller, MD:

A patient can go online, sign up, it's sort of like a home pregnancy test in a way.

Raed Dweik, MD:

Yes, that's impressive. For an unrecognized disease, that's almost the only way to make sure that we recognize more and more of these patients. And that takes me to my next question which is, why is it important to recognize this? You know, do we want to diagnose it? Are there effective therapies for this? And how do they work?

Jamie Stoller, MD:

First of all, we recognize that delayed recognition is associated with worsened clinical outcome. A paper published by our colleague, Vic Tejwani and I showed that diagnostic delay interval was directly associated with worsened cat score, worsened in St. George's respiratory questionnaire, and a trend towards a lower FEV1. So diagnostic delay is ill advised in a progressive disease.

We also know, as you suggest, that there are interventions even short of specific therapy, for example, smoking cessation. In the studies done at birth, in Sweden and in this country, individuals tested at birth, identified at birth had a lower likelihood to ever initiate cigarette smoking in their teens than did their age and gender matched normal colleagues. So smoking prevention is very important. Occupational choice: it would be ill advised to be a coal miner exposed to dusty environmental, exposures with alpha-1. So there are those interventions.

Of course, all the usual interventions in chronic obstructive pulmonary disease for patients who are afflicted apply, with the possible exception of lung volume reduction surgery, where we know from a subset analysis of the Net trial in which we at the Cleveland Clinic, as you know, participated, we identified that individuals with alpha-1 undergoing lung volume reduction surgery tend to experience lower increments in their FEV1 of shorter duration than their normal matched colleagues. So with that possible exception, all of the other interventions, bronchodilators, supplemental oxygen, vaccinations, pulmonary rehab, certainly apply.

Lung transplant, in extreme cases, is clearly available. And about 5 percent of lung transplants performed worldwide are performed for individuals with severe COPD due to alpha-1 antitrypsin deficiency. Beyond that, there are specific therapies. And the specific therapy is called augmentation therapy, which in the current state is the intravenous infusion of pooled human plasma derived alpha-1 antitrypsin. So donors give blood, that blood is highly extracted, purified, and the alpha-1 component extracted, prepared in either a lyophilized preparation or several liquid preparations, and then is given intravenously to these individuals once weekly at a dose of 60 milligrams per kilogram, which is the FDA approved dose and dosing interval, for life.

We do know, from now three randomized clinical trials, the weight of evidence suggests that such therapy is effective in slowing the rate of COPD progression as assessed by CT densitometry in the most recent so-called rapid trial. But the weight of evidence is clear even though no one individual randomized trial, which is always a challenge in a rare disease, assembling a large enough cohort to have adequate power, et cetera. Although no one randomized trial in my view is definitive, the weight of evidence is quite clear that augmentation therapy is effective, and I certainly prescribe it in my practice.

Raed Dweik, MD:

It's always great to have effective therapies for these chronic illnesses. It's not as unusual, because other types of COPD don't have specific therapies, so it's maybe more incentive to make the diagnosis because you have a specific treatment as opposed to just the usual oxygen inhalers, et cetera. Are there any family implications for making the diagnosis?

Jamie Stoller, MD:

Yes.

Raed Dweik, MD:

Genetic disease. So what are the family implications?

Jamie Stoller, MD:

Yeah, so guidelines similarly suggest since this is, again, an autosomal codominant condition, the gene lives on the 14th chromosomes, so it's not sex linked. And because it's an autosomal codominant condition, that means guidelines suggest that every first degree relative, parents, if they're living, all siblings, and all children should be tested. So for example, in one scenario we know that heterozygotes, one normal gene M and one abnormal gene Z, MZ individuals comprise 3 percent of Americans. So in the case of an MZ father and an MZ mother, there's a one in four chance of that parentage that a child as an independent risk reached child will be ZZ or homozygous, a two in four chance that the child will be MZ, and a one in four chance of being MM normal.

We also recognize that MZ individuals, if they smoke, are at risk for developing emphysema, probably more pronouncedly than if they were MM. And smokers, some recent data from COPDGene and other studies support that idea. And so this is a family affair. And patients that I see who are afflicted, become spokespersons to their families and promote this. We also know from studies done with, again, these gene testing companies, recently published in that the diagnosis made has implications for reporting to family members and to their physicians. So that rendering a diagnosis is impactful for the patient, him or herself, and for his or her relatives.

Raed Dweik, MD:

Yeah, it's important to know because the implications is not just for the individual, but all the entire family is affected. So are there any novel treatments coming down the pike for this disease or is it just augmentation therapy?

Jamie Stoller, MD:

No. We've had augmentation therapy since the late 80s, the first such drug, there are four approved in the United States today. But thankfully, there are other approaches that are quite novel. And they run the gamut from corrector molecules, much like our approach to cystic fibrosis, to molecules that amplify the impact of the alpha-1 sort of like antibodies with two headed alpha-1 molecules that have longer half-lives, to gene editing approaches, to gene therapy trials, to this RNA editing, DNA editing. There are a number of very novel approaches.

CRISPR is being looked at in murine models currently, and so that I expect that, over the course of the next decade, of course hard to absolutely predict, but my expectation is that over the course of the next decade, some of these novel therapies will come to fruition and gain approval, in pivotal trials and so on.

Raed Dweik, MD:

Wow, that's exciting. Always new things coming down the pike. So there is hope.

Jamie Stoller, MD:

Absolutely.  Another reason to make the diagnosis. So that even though augmentation therapy may be an unsatisfactory current approach, there are prospects in the near future, I predict, that will be available for therapy.

Raed Dweik, MD:

Thank you. This has been really very informative, Dr. Stoller. Any closing remarks or anything you like to close with?

Jamie Stoller, MD:

Well, I appreciate the opportunity to chat with you about this. This has of course been an area of major personal focus and focus for us at the Cleveland Clinic for a long time. I would emphasize perhaps three takeaway points. One, this is common and under-recognized. Two, there are specific therapies which have impact for the patient. And three, this is a family affair because of its genetic nature. You're treating the patient in front of you in your office and his or her family at the same time.

Raed Dweik, MD:

Wonderful. Thank you so much. I really appreciate you taking the time today. And thank you to our audience for listening. Again, this is your host, Raed Dweik, the chairman of the Respiratory Institute at Cleveland Clinic. And my guest today was Jamie Stoller, who is the chairman of the Education Institute at the Cleveland Clinic and also a nationally and internationally known expert in alpha-1 antitrypsin deficiency, which was the topic of this podcast. Thank you and have a great day.

Thank you for listening to this episode of the Respiratory Exchange. For more stories and information from Cleveland Clinic Respiratory Institute, you can follow us on Twitter @CleClinicLungs or follow me @RaedDweikMD. Thank you.