Diagnostic Challenges and Clinical Pitfalls in HAE

Dr Allen Kaplan reviews common diagnostic pitfalls in hereditary angioedema, including misinterpretation of complement testing, confusion with histaminergic angioedema, and challenges in identifying HAE with normal C1 inhibitor. This expert discussion offers practical guidance for allergists to shorten diagnostic delays and avoid misdiagnosis in clinical practice.

Allen P. Kaplan MD, Clinical Professor of Medicine at the Medical University of South Carolina (MUSC) in Charleston, South Carolina, United States.

Transcript

Hi, I'm Dr Allen Kaplan. I'm an affiliate professor of medicine at the Medical University of South Carolina. One of my major areas of interest is the pathogenesis and treatment of hereditary angioedema. And I had spent much of my academic career researching the bradykinin-forming cascade. And it turns out, of course, that bradykinin is the cause of the swelling in hereditary angioedema. So the connection between the two is obvious and is the reason why I'm often asked to comment or speak about hereditary angioedema.

What are the most common diagnostic pitfalls you see when evaluating patients for HAE, particularly in community or non-specialty settings?

Dr Kaplan: Yeah, I think that the definition of hereditary angioedema or what leads you to think of it, is not just having a difficult patient to treat. There are patients with angioedema and no hives who are tough to treat. That doesn't mean it's hereditary angioedema, but it means that you have to have alternative drugs to use in that circumstance. But I think that for the other types of angioedema, if there's no family history and no hives and a normal C1 inhibitor and a normal C4 and no laryngeal edema and no GI attacks, then it's most likely not hereditary angioedema. And I mentioned that there now are forms of hereditary angioedema where the C1 inhibitor and the C4 are normal. So they're called HAE with normal C1 inhibitor, but they are very rare. The incidence is one in hundreds of thousands of people. So one has to be aware of that as a possibility.

It is helpful if they have a family history. They may lack the other manifestations, but if they have a family history, you could suspect it. There is no simple test for these alternative disorders. If you think of it, you need to say, send blood to specialized laboratories who can detect alternative mutations to that of C1 inhibitor. And the 2 most common are a mutation in factor 12 and a mutation in plasminogen. There are actually eight of them that are HAE with normal C1 inhibitor, but certainly if you live in the United States, those two out of the eight will be the ones that you are more likely to encounter bearing in mind that they're very rare to begin with.

How should allergists approach laboratory testing when HA is suspected? And what are the most frequent mistakes in ordering or interpreting complement studies?

Dr Kaplan: The C4 is low in 95% of patients, even when they're normal, meaning they're not having an attack of swelling. They just come in, your physical exam is normal, but they give you a history of recurrent angioedema. It sounds like it could be HAE. You do the C4 and it will be low 95% of the time. So of course, one in 20 will give you a normal C4, so you have to watch out for that. If you catch them with an attack of swelling and they have HAE, then the C4 is low in almost 100%. So it drops further when you're symptomatic. The other thing is, of course, it's due to C1 inhibitor deficiency. So you send blood to measure C1 inhibitor by protein and by function. 

Now, why do we do both of these? Because in C1 inhibitor deficiency, there are two types, which of course we called Type 1 and Type 2. Type 1 is 85%, Type 2 is 15%. So the difference is in the nature of the mutation. In Type 1, the mutation that the person has, leads to a very low amount of the protein in the circulation. In other words, they are not producing C1 inhibitor or it's not being liberated from the liver, for example, into the circulation. So the protein is low, and of course the function will be commensurately low with the protein. That's Type 1. Type 2 has a mutation such that the protein is produced and secreted. So the protein level is normal, but the mutation involves the active site of C1 inhibitor and it's not functional. So we do both. So Type 2, which is a little harder to diagnose, still may have a low C4 and 95% of patients, and then it will have a normal C1 inhibitor by protein, but a quite low C1 inhibitor function. Then you have diagnosed Type 2 hereditary angioedema. The therapy of these 2 types are exactly the same.

In patients with normal C1 inhibitor levels and function but persistent symptoms, how do you decide when to pursue HAE with normal C1-inhibitor versus alternative diagnoses?

Dr Kaplan: Yeah, that's what we have alluded to. It's really a tough diagnosis. So you have a patient whose C1 inhibitor and C4 are normal. They have recurrent angioedema. If they have laryngeal edema in their history or abdominal attacks that sound like HAE, then they might have this HAE with normal C1 inhibitor. If they give you a positive family history, of course, maybe then that becomes what you are dealing with. 25% of patients with C1 inhibitor deficiency do not have a family history. We do not know if patients with HAE with normal C1 inhibitor who have a different mutation, we don't know if 25% won't give you a family history. There is no data on that. So you do rely on a family history to clue you in to the fact that it's quote hereditary angioedema and not non-hereditary angioedema.

So let's say now that the patient has maybe a family history, that would be enough to consider it or no family history, but they have angioedema with no hives, it's recurrent, and they have either the laryngeal edema or abdominal attacks or both that would lead you to consider HAE with normal C1 inhibitor when you've gotten a normal C4 and C1 inhibitor. If you encounter that, you have to be familiar as to what are the alternative mutations in HAE with normal C1 inhibitor. There are 8 different types, not going to go through all of them, but just mention 2 that are well understood, much better than the others, and are more likely to occur in a patient, particularly in the United States. That's a mutation of factor 12 and a mutation of plasminogen. And if you suspect HAE with normal C1 inhibitor, blood needs to be sent to a laboratory that is capable of doing the genetic assay to look for the mutation. It's the only way to diagnose those disorders. You have to look for the mutation.

When C4 and C1 inhibitor results are borderline rather than clearly diagnostic, what guides your decision to pursue C1 inhibitor genetic testing?

Dr Kaplan: Well, the C4 and C1 inhibitor tests are really good tests. And in most patients with hereditary angioedema, you don't have a problem. But your question is, when do you actually look for the C1 inhibitor mutation? I would say that the most common reason for looking for the mutation is when the levels of C4 and C1 inhibitor are low, but only a little low and not low enough to make the diagnosis obvious. Let's say a borderline level. A typical C1 inhibitor level in a patient with hereditary angioedema is less than 15% of normal. So it's usually between zero and 15%. Let's say you had a patient, and it came back 45% of normal. Well, it's certainly not normal. It's a little bit less than half normal, and you can't be sure, maybe in that circumstance, what you're dealing with.

Although if you had a good family history, maybe you would then interpret it as being consistent with hereditary angioedema. But let's say you didn't have such a good family history, or let's say you had a patient with Type 2, that's the 15% where the protein is normal, but the function is abnormal, and you get a function of 45%. So you may be unsure. Does that patient really have a hereditary form of angioedema? That's the time to send blood looking for a C1 inhibitor mutation. That one most laboratories are capable of doing. It's not kind of new or esoteric like the HAE with normal C1 inhibitor, but that is the circumstance in which you would do it.

From a practical standpoint, what strategies can help shorten the diagnostic delay for HAE and prevent unnecessary treatment or emergency visits?

Dr Kaplan: Yeah, I think that there is often a very long time from when a patient first presents with HAE and has symptoms and the time of diagnosis. It's not too long ago that it was close to 7 or 8 years of floundering and not being sure what it is and seeing a variety of doctors, and then finally making the diagnosis. I see it all the time, and I don't feel that it's really all that difficult, but I think the most important thing is that the C4 and C1 inhibitor tests are not particularly expensive. I don't think they should be done unless there's a reasonable reason to do so. But if a physician is uncertain what they're dealing with, there's no reason not to get the C4 and C1 inhibitor. And that will allow the diagnosis of some patients who might not be obvious, but then the diagnosis is made.

And we have discussed what makes you think of HAE versus not having HAE, but there are many physicians in practice who don't have that much experience treating patients with angioedema. And that's why sometimes the patient flounders in terms of getting a specific diagnosis. And it's very important because we know how to treat HAE. There are many drugs now that one can use. So my feeling is that, okay, when maybe the first time the patient comes to a physician or an allergist like me with a history of recurrent angioedema, you may or may not make the diagnosis on that first visit. But if they come back with a second visit with a recurrent angioedema, that's the time to make the diagnosis. For example, if somebody comes to me with angioedema, but they've only had one attack, I'm not going to draw a C4 and a C1 inhibitor. There's not usually enough information to do that unless they have a blatantly obvious family history. But if they come back a second or a third time, I would immediately draw it, assuming it fulfills the criteria we just discussed, and not having hives and having other manifestations that give you a clue to having hereditary angioedema.

Are there any insights you would like to share with allergists regarding diagnostic challenges and clinical pitfalls in HAE?

Dr Kaplan: I think that the most important thing is distinguishing in your mind what is common and what is uncommon, and what are the manifestations of each. There are people who have acute angioedema. That may be just one episode. They're allergic to some drug that they're taking or even a food allergy, although usually they would have hives with their angioedema. But let's say now the person has recurrent angioedema with no hives or recurrent angioedema with hives, which is the most common. Those are most likely going to be either chronic spontaneous urticaria with angioedema, which is the angioedema in 40% of patients, or they're going to be one of the less common entities where they have recurrent angioedema that's histamine-mediated, but they're not having hives with it. And even though that is less common than the urticaria patients with angioedema, it's much more prevalent than hereditary angioedema.

So you would try, I think therapy helps you, and that is, do they respond to antihistamines? And you can go up to 4 times a day of your favorite antihistamine.
If they are refractory to antihistamines, you can try Xolair as the next. HAE will not respond to it, but the other kind of angioedema will. And now that allows you to use treatment to help you make the diagnosis retrospectively when you're otherwise might not be sure. That's the important thing to remember, and that HAE doesn't have urticaria, is resistant to antihistamines, does not respond to Xolair, and even does not respond to epinephrine. All that is the opposite of the other types of angioedema that we see, the exception being the ACE inhibitor, because that's bradykinin-mediated that looks like HAE.