Differentiating Hereditary Angioedema From Its Mimics

Dr Allen Kaplan, MD, discusses how to distinguish hereditary angioedema from common angioedema mimics, including histaminergic and ACE inhibitor–associated angioedema. This expert-led discussion reviews key clinical features, diagnostic testing, and bedside clues to accurately identify bradykinin-mediated angioedema in urgent and routine 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.

In your experience, which angioedema mimics most commonly lead to misdiagnosis of hereditary angioedema, and why are they so frequently confused in clinical practice?

Dr Kaplan: Yeah. Because it's a rare disease, many people are not familiar with the presentation of hereditary angioedema. And it turns out that what I might call ordinary angioedema is reasonably common. So when a hereditary angioedema case appears, it's going to be one of many angioedemas that any physician might be seeing. And you have to be aware of what the differences are. In hereditary angioedema, first of all, when taking a history, one of the first questions is, is there a family history of angioedema? 75% of patients will say yes, and they will give you the history, parents, siblings, and children and so forth. But 25% will not have a family history and still might have the disorder. We think those individuals are probably people with a new mutation. So their parents and siblings wouldn't have it, but their children might. And so then if you suspect hereditary angioedema, then the two tests that are requisite to be done is a C4 level, which is diminished in 95% of patients.

And then C1 inhibitor, which is the protein that is dysfunctional in hereditary angioedema. And we measure it in 2 ways, first as a protein, and secondly, as a function. And what clues you in to doing this, because I certainly wouldn't order them on every angioedema patient that comes. So the characteristics of hereditary angioedema are that there are three kinds of swelling people have, peripheral, which overlaps with other kinds of angioedema, meaning the face, lips, sometimes tongue, extremities, and sometimes genitalia. The swelling, rather than being itchy, has a burning type of pain at times and may last longer than the angioedema that is mediated by histamine.

However, hereditary angioedema patients have 2 features that are not seen with angioedema of other causes. One of them is abdominal attacks. They have edema of the bowel wall, and the symptoms that cause it are severe pain, often vomiting, and sometimes diarrhea. And it lasts two or three days. It's quite severe and leads people to go to the emergency room. That differs from abdominal symptoms of other causes, like irritable bowel syndrome. So they have these gastrointestinal attacks, and they are common in patients with HAE. The other are laryngeal attacks. Laryngeal attacks in the lifetime of a person happen sooner or later in most people, but they may be few and far between, hopefully. Laryngel attacks are potentially fatal. They have edema of the vocal cords and surrounding larynx, which can lead to asphyxiation. You do not see that with the angioedema of other types.

Now, one of the questions that has to be asked of patients is, are you taking a therapy, angiotensin converting enzyme inhibitors? Because that drug causes angioedema that is bradykinin-mediated, not histamine, and can be confused with hereditary angioedema. It would not have a family history. The C4 and C1 inhibitor would be normal, and you're looking for a history of a drug reaction. One of the defining features of that is the swelling, in slight contrast to hereditary angioedema, is more common facially. They really have prominent facial swelling, lip swelling, tongue swelling, and possibly laryngeal edema. Laryngoedema is a manifestation of bradykinin-mediated angioedema. Most other angioedemas do not have laryngeal edema and therefore will not have a family history of people asphyxiating, for example, which sometimes is related when you take the history.

What key clinical features help distinguish bradykinin-mediated angioedema from histaminergic angioedema at the bedside, particularly in urgent or emergency settings?

Dr Kaplan: Yes. I covered that partially, but to summarize it, the peripheral swellings are, I believe, sort of more severe, although that's subjective. They do not itch, and they may have a burning, painful quality associated with them that other kinds of angioedema, particularly those mediated by histamine, do not have. But unique to hereditary angioedema, apart from other angioedemas and common with all bradykinin-mediated angioedemas, are the gastrointestinal attacks I mentioned and the possibility of having laryngeal edema. That's, of course, dangerous. It needs to be treated immediately if it's suspected. People, even with treatment, often go to the emergency room for safety to make sure that they don't need an intervention to help them breathe.

How reliable are associated symptoms—such as urticaria, response to antihistamines, or presence of pain—in differentiating angioedema subtypes?

Dr Kaplan: Oh, if you get a good history, it's very important. In angioedema that is mediated by histamine. The most common, if it's persistent angioedema, is what we call chronic spontaneous urticaria. 40% of those patients have angioedema associated with it. So they are having hives and occasional angioedema. That angioedema can be peripheral, like hereditary angioedema, but not the GI tracts and not laryngeal edema. Hereditary angioedema patients, generally speaking, do not have hives. So if you have a patient in general with hives and angioedema that come and go over a long period of time, it's unlikely to be hereditary angioedema. We have learned that there is an exception, but there are 2 very rare kinds of angioedema that is hereditary, but not due to C1 inhibitor deficiency. One of them is a mutation in a protein called carboxypeptidase N.

C1 inhibitor deficiency is about one in 20,000 to 50,000. And the one I'm referring to is maybe 10% of that one in 500,000 or so. So it can occur in that type. In one other, that's rare where you would have urticaria with angioedema and it would be hereditary. There are really rare exceptions. Most people go through an entire career without ever encountering one. So I would say generally speaking, if a person has obvious urticaria with their angioedema, do not think of hereditary angioedema unless they give you a family history that's believable. Then it's probably a chronic spontaneous urticaria with angioedema or some other diagnosis, but that would be the most common alternative.

For patients with recurrent angioedema without wheals, what diagnosis should allergists systematically consider before labeling a case as HAE?

Dr Kaplan: Yeah. Well, still, the most common is not going to be HAE. There are patients in which the angioedema is mediated predominantly by histamine without hives. Its incidence maybe is 10% or 15% of that of chronic spontaneous urticaria with angioedema. So this is sort of an angioedema alone. It will respond to antihistamines. It will respond to Xolair, which we haven't talked about yet, but it's a monoclonal antibody to IgE, and it's almost a hundred percent responsive to that. If in an acute situation, epinephrine will work to at least abort an attack; all of those things don't happen in hereditary angioedema. And of course, these people in general will not have a family history. So you would have recurrent angioedema without hives, no family history, normal C4 and normal C1 inhibitor if you choose to measure it, and it's reasonable to measure it if the patient has no hives, but they will be normal and no laryngeal edema, no clear abdominal attacks, and responsiveness to antihistamines and Xolair. That distinguishes it from hereditary angioedema.

How do medication-related causes, such as ACE inhibitor-associated angioedema, complicate the diagnostic evaluation of suspected HAE?

Dr Kaplan: Yeah. The angiotensin converting enzyme inhibitors are prescribed for a variety of reasons. The most common is hypertension, but also congestive heart failure, and rarer patients with acute attacks with scleroderma, which is an autoimmune disease, but nevertheless, the drug is used. And so the history will be that somebody is taking an ACE inhibitor for one of those reasons. In contrast to some allergic reactions to drugs, where maybe the second or third time that you're taking the drug, suddenly you become allergic and have a reaction. You can have a patient on ACE inhibitors for years, and they tolerate it, everything is good, and then suddenly they start having angioedema to the ACE inhibitor. That angioedema appears to be bradykinin-mediated, although the data in favor of it are not as rigorous as it is with hereditary angioedema, where we know kind of 100% that that is the mediator.

The ACE inhibitor patients can have asphyxiation. They can have laryngeal edema. They can also have tongue swelling that is so severe. The tongue is so big that they can't handle their own secretions and they choke on it. So ACE inhibitor angioedema can be fatal. If you diagnose it, acute treatment can be tried with an anti-bradykinin drug like Icatibant. It would not respond to Xolair or other things that we use for C1 inhibitor deficiency, but since they are both mediated by bradykinin, a bradykinin antagonist can buy you some time, but those patients need to be whizzed into the emergency room and watched. Sometimes they need to be intubated, and of course, the ACE inhibitor needs to be stopped and some other drug used to treat whatever they were treating initially.