Alpha-1 Antitrypsin Deficiency: Bridging Care
Transcript: The role of primary care in AATD
James Stoller, MD, MS
All transcripts are created from interview footage and directly reflect the content of the interview at the time. The content is that of the speaker and is not adjusted by Medthority.
Primary care physicians are critical in diagnosing alpha-1 antitrypsin deficiency because most patients who are affected by alpha-1 antitrypsin deficiency, whether liver or lung, actually see primary care doctors. The data in North America are that fewer than 15% of patients with chronic obstructive pulmonary disease, one of the manifestations of alpha-1 antitrypsin deficiency, see pulmonologists, meaning that the majority of such patients are followed by primary care doctors. In the liver literature, patients with compensated cirrhosis, hepatocellular carcinoma, the data suggests that perhaps only half of those patients actually see hepatologists or gastroenterologists, and that the other half or more see primary care doctors. So primary care physicians are at the front line of diagnosis in alpha-1. That's the reason they're so important. Well, of course, primary care physicians have a challenging job because patients come with a whole array of signs and symptoms. In the case of alpha-1 antitrypsin deficiency, of course, pulmonary manifestations are the most common clinical presenting features. Patients present with chronic obstructive pulmonary disease, chronic bronchitis, such patients would characteristically be short of breath as a common presenting symptom. And in those instances, the primary care physician would be wise to order pulmonary function tests. Do simple tests like spirometry. And in finding fixed airflow obstruction, that is to say, a ratio of the FEV1 to FVC less than 0.7 or less than the lower limit of normal after administering bronchodilators. Such patients would be defined as having chronic obstructive pulmonary disease. Every patient with COPD or chronic obstructive pulmonary disease should be tested according to guidelines for alpha-1 antitrypsin deficiency. In the case of liver disease, which affects perhaps up to 40% of patients with alpha-1 antitrypsin deficiency of certain genotype, most commonly, PiZZ type, which is, of course, the most common severe deficient genotype. Patients with liver disease may present with non-specific symptoms. Arthralgias, obviously jaundice in advanced stages, fatigue, lethargy. And in that instance, the primary care doctor will likely be checking liver function tests. And of course, there are some composite liver function tests like the AST to platelet ratio and others that are a little bit more sophisticated, and that might give some insight into the presence of cirrhosis. In any event, if the primary care doctor were to order a liver function test, and they were abnormal, then one would either refer to a gastroenterologist hepatologist or perhaps do other confirmatory tests to evaluate that, like vibration-controlled transient elastography or FibroScan, which is a test that evaluates scarring of the liver.
So these are the common pathways to diagnosis of alpha-1. Of course, it's also important to emphasize that because this is an autosomal codominant condition, a genetic condition, in taking a family history and learning that a family member has emphysema and/or cirrhosis, one might have a heightened suspicion in the patient in front of you who offers a family history of that nature. So those are the common clues, if you will. The most useful tests are, number one, a clinical suspicion. Of course, that goes without saying. But having suspected alpha-1, the primary care doctor could simply check a serum level for alpha-1 antitrypsin, and ideally a genotype, which is often a PCR-based test, a blood test that will evaluate most commonly four alleles, and in some instances, up to 14 alleles, looking for the most common variants. So these are the confirmatory tests when one has a suspicion of alpha-1 antitrypsin deficiency. Begins with clinical suspicion. And when one has a clinical suspicion of the presence of alpha-1, one might, from a liver point of view, check liver function tests, a routine liver panel. It's clear that such tests may be relatively insensitive for the presence of alpha-1 antitrypsin deficiency, but nonetheless, when abnormal, should certainly prompt further testing. And elevated hepatocellular enzymes, AST, ALT, et cetera, could be indicative of a whole differential diagnosis of liver conditions. Not only alpha-1 antitrypsin deficiency, but hepatitis of various viral hepatitis, Wilson's disease, hemochromatosis. And the primary care doctor would, in the face of abnormal liver function tests, then initiate a more exhaustive workup of the cause of that liver dysfunction. Of course, alcohol as well. And, in many instances, might then make a referral to a gastroenterologist or hepatologist who would do perhaps more specific testing, including, as I said, the vibration-controlled transient elastography or FibroScan, which is a test focused on the degree of fibrosis of the liver. Remembering that alpha-1 antitrypsin deficiency can cause liver scarring or fibrosis, which may progress, of course, to cirrhosis. AlphaDetect is an exciting new development in the world of alpha-1 antitrypsin deficiency. It stems from the fact that most patients with alpha-1 antitrypsin deficiency, and this is true globally, are under recognized. In the United States, perhaps fewer than 15% of 100,000 individuals who have severe deficiency, PiZZ genotype, are clinically detected. And similar numbers come from, again, all over the globe. So given the severe under recognition of alpha-1 antitrypsin deficiency and the fact that delayed diagnosis is associated with more advanced disease, there is a clear imperative to recognize alpha-1 antitrypsin deficiency early. Many efforts have been made over time, and the most recent, and perhaps most exciting from my point of view, is AlphaDetect. AlphaDetect is an organization that's been spawned as a wholly-owned subsidiary of the Alpha-1 Foundation, whose primary purpose is to detect every individual with alpha-1 antitrypsin deficiency. And it will do so through raising awareness of alpha-1, and then most importantly, by making testing free and available to all individuals. Individuals, physicians, perhaps even in collaboration one hopes with pharmacies and other entities that are prescribing medicines for patients with liver and lung disease.
Now these are very early days of AlphaDetect, the test kit has not yet been fully prepared. We expect that to happen over the next few months. And you'll be hearing much more about AlphaDetect over the ensuing period of time. Expect the first few months of 2026. So very early days, but very exciting. Gets back to the clinical suspicion of alpha-1. And when a primary care physician suspects alpha-1, and perhaps tests for alpha-1, if the test results shows severe deficiency of alpha-1, again, most commonly, the PiZZ type, although we must remember that there are more than 200 abnormal alleles for alpha-1 antitrypsin deficiency. The most common wild type is, of course, the PiMM genotype, which is normal. And the PiZZ genotype, a single amino acid substitution at position 342 of the 394 amino acid protein that is alpha-1 antitrypsin. Finding a PiZZ genotype, or perhaps even a PiSZ genotype, might prompt referral of that patient to perhaps both a pulmonologist for further assessment of lung function and so on, and also perhaps to a gastroenterologist or hepatologist for further assessment of liver function. Liver and lung are the most commonly affected organs in alpha-1 antitrypsin deficiency of the most common severe genotype, PiZZ. There are other less commonly associated conditions, one of which is panniculitis. So patients with alpha-1 may occasionally be seen by dermatologists as well. And in working up panniculitis, which is an inflammatory condition of the skin, the primary care physician might refer then to a dermatologist. There is also a very interesting association with what we call granulomatosis with polyangiitis or C-ANCA positive vasculitis. And perhaps the odds ratio of finding an abnormal alpha-1 genotype among patients with GPA or granulomatosis with polyangiitis is about 11. So that primary care doctors seeing such patients with GPA might also want to test for alpha-1 and perhaps make referrals in that case to physicians who care for the end organ effects of GPA, which may be the kidney, the sinus, et cetera, the lung, et cetera. My primary piece of advice would be to keep alpha-1 antitrypsin deficiency top of mind as an explanation for COPD, for liver disease, and to do so whether or not the patient presents with alternative explanations of liver or lung disease. For example, in seeing smokers, one may attribute the COPD in the patient to smoking, but of course, smoking only accelerates the effects of alpha-1 antitrypsin deficiency because it increases the proteolytic burden to the lung. And so one should not suspend suspicion for alpha-1 in seeing a patient with COPD who's been a smoker.
Similarly, one should not suspend suspicion of alpha-1 antitrypsin deficiency in the patient who has an extensive alcohol history, or even viral hepatitis, because alpha-1 may still underlie the liver disease in such instances. So keeping alpha-1 antitrypsin deficiency top of mind, remaining aware of the genetic implications, testing not only the patient in your office, but then detecting a patient who has severe deficiency of alpha-1 and testing their family members, first-degree relatives, siblings, parents, children. These are the key pieces of advice that I would offer a primary care physician. I think there's ample information to suggest that there's a knowledge gap with regard to alpha-1 antitrypsin deficiency. A number of studies, including the ones that we've done in my own institution, have shown that physicians in training, respiratory therapists, even specialists in some of the literature, whether lung specialists, liver doctors, have a gap in their knowledge of alpha-1. And so keeping aware of alpha-1 as a relatively common cause of COPD or liver disease is a key step. And of course, drilling down on the cause of that knowledge gap, one needs to keep alpha-1 in the forefront in medical education. So resisting the idea that the only patients with alpha-1 antitrypsin deficiency are young individuals who've never smoked and who have lower lobe emphysema. These are classic presentations of alpha-1, but they're by no means the most common. And so educating physicians in training of the full array of alpha-1 antitrypsin related signs and symptoms, and then having physicians keep this in mind in their practice. These are the key things that I would change.
Developed by EPG Health. This content has been developed independently of the sponsor, Takeda, which has had no editorial input into the content. EPG Health received funding from the sponsor to help provide healthcare professional members with access to the highest quality medical and scientific information, education and associated relevant content. This content is intended for healthcare professionals only.
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