All about HAE with normal-C1 inhibitor

An increasingly important aspect of HAE management and advocacy is to support a very special group in our community, Tony Castaldo told the assembled HAE advocacy leaders. For that reason, he welcomed Professors Sandra Christiansen, Marc Riedl, and Bruce Zuraw onto the stage. All three specialize in the care of people with HAE at the University of San Diego and were central to the HAEi and HAEA-supported efforts to develop expert consensus on the diagnosis and management of people with HAE with normal C1, published in 2025.

Tony facilitated the discussion around a set of key questions. Tony started by asking Dr Riedl about the differences between HAE with normal C1 inhibitor and HAE with C1 inhibitor deficiency or dysfunction. Dr Riedl indicated some key elements:

• People get severe protracted angioedema symptoms, but the first difference is that HAE with normal C1 affects many more women than men
• HAE with normal C1 inhibitor seems very sensitive to the hormone oestrogen, to the extent that occasionally removing any oestrogen-containing medication is enough to stop the symptoms
• The onset of symptoms seems to be during adult life, after the 20s and into the 30s and 40s. It differs from HAE types 1 and 2, which are more commonly seen first in children and teenagers.
• The location of the swelling seems to be different. With HAE with normal C1, there is more facial, head and neck swelling, and less abdominal symptoms and extremity swelling. For instance, in one variant called HAE plasminogen, there are prominent tongue swellings.
• Patients with HAE and normal C1 are less likely to have a strong family history, Dr Zuraw added. Men may be less affected and therefore appear to be ‘silent carriers’.

Dr Zuraw outlined the diagnostic criteria for HAE with normal C1 inhibitor. He acknowledged that diagnosis has long been a concern in the community. He said: “In a nutshell, we don’t have a good way to make it so you go in and see a doctor and walk out knowing the diagnosis. It’s a series of steps that the doctor and patient have to go through.” He outlined the steps as:

• If someone has recurrent angioedema, we measure C1 inhibitor and C4 to exclude HAE types 1 and 2.
• If that comes back negative, we will trial drugs for mast-cell (allergic) angioedema to see if they help. If that doesn’t work, then medicines such as montelukast or omalizumab are tried. All of this may take many months to rule out mast-cell involvement.
• If a strong family history is identified, the diagnostic path might immediately turn to genetic testing.
• Finally, medicines like icatibant are used to see if attacks respond. Genetic tests will likely be done at the same time. If the medicines work, then it’s bradykinin sensitive and an initial, tentative diagnosis of HAE with normal C1 inhibitor can be suggested. Then, if a known genetic mutation is identified, it can be confirmed.

Dr Christiansen reflected that the length of the answer Dr Zuraw needed to give was an indication of how complex it is to receive a diagnosis of HAE with normal C1. She described the need for biomarkers and laboratory tests that could confirm the presence of this type of HAE in a person. As mentioned earlier, a family history can even complicate things due to ‘incomplete penetrance’ (meaning that not everybody who you might think will exhibit the disease will show it). There are only six currently measurable genes and two more that also lead to hives, which means only a very small fraction have a known genetic variant.

Building on this, Dr Christiansen discussed the importance of genetic testing in HAE with normal C1 inhibitor. It varies greatly depending on where someone lives and the access to the tests. In the US, genetic testing is available, but even as it becomes more affordable, it remains out of reach for some people and some countries.

To the follow-up question, ‘Why is it important to look for genetic mutations?’ Dr Christiansen responded that if a faulty gene is found, it will be important to screen everyone in a family.

Turning to Dr Riedl, Tony asked why so many genes are implicated in HAE with normal C1 inhibitor. In his response, Dr Riedl referenced the six known genes and two others that may be involved. He described the system, which you can read about in Professor Li’s talk, as complicated, with many different places where it can go wrong, leading to problems with the bradykinin system and swelling attacks. He reminded the audience that historically, HAE with normal C1 might have been called type 3 HAE, but it is not a single type of HAE; rather, it is an umbrella term for many different genetic conditions.

The next question posed to Dr Zuraw was ‘What is the mediator for swelling in HAE with normal C1 inhibitor?’ Dr Zuraw highlighted that scientists are clear it’s not mast cells, and bradykinin is suspected as the mediator, borne out by the fact that medicines like icatibant seem to have an effect. Dr Zuraw said: “At the heart of it, I think, will be bradykinin.”

If a family doesn’t have a history of known mutation, what type of angioedema do they have? 

Dr Christiansen reminded the audience that even with HAE type 1 or 2, there is a one-in-four chance that no one else in a family will be affected. Some patients will have had a ‘de novo’ mutation in their genes, causing HAE. So, in HAE with normal C1, some patients may have no family members affected before. It may also be that some people, especially men, may have the gene defect but show no symptoms.

Tony asked: What are the on-demand treatments for HAE with normal C1 inhibitor?

Dr Riedl returned to the use of icatibant, as an indication that doctors use similar medicines as those for HAE with C1 deficiency or dysfunction. It includes C1 inhibitor concentrate and, in the US, ecallantide. Doctors lack large studies showing how effective these medicines are in HAE with normal C1, but the available data indicate that these medicines work about the same as in HAE types 1 and 2. In a similar vein, Tony asked about prophylaxis options for HAE with normal C1 inhibitor. Dr Zuraw suggested that, similar to on-demand, doctors largely turn to medicines developed for HAE due to C1 inhibitor deficiency. The main difference is tranexamic acid, which inhibits plasmin production, and this is useful because plasmin seems to generate bradykinin in HAE with normal C1. Additionally, due to the female focus of the disease, addressing levels of oestrogen, perhaps with progestin-only contraceptive pills, can help prevent attacks.

Taking this discussion further, Dr Christiansen suggested that with the Factor 12 variant, progestin appears particularly effective. The point of all this, Dr Christiansen said, is that as understanding improves, the likelihood of developing effective therapies will increase.

Still talking treatment, Tony asked: Why do treatments for HAE with C1 inhibitor deficiency work for HAE with normal C1? Using a video game analogy, Dr Christiansen suggested that in HAE with normal C1 inhibitor, the C1 inhibitor is swallowed up, or used up, during an attack.

Are there any clinical trials for HAE with normal C1 inhibitor?

The short answer, according to Dr Riedl, is no. Some patients were included in larger studies of ongoing treatment, but because diagnosing people with HAE with normal C1 inhibitor is difficult, there haven’t been any large clinical trials. At present, the focus is on ensuring reliable diagnostic tools are available before trials begin.

Might a laboratory test become available to make diagnosing HAE with normal C1 inhibitor easier?

Dr Zuraw acknowledged that this would be a Holy Grail, enabling accurate and quick diagnosis, but the answer is not yet. For a few patients, the genetic tests provide an answer. There are lots of people working on tests. Dr Zuraw concluded that he is hopeful, “I have to be optimistic that we’ll be able to develop such a test and finally be able to be much more effective in how we manage this disease.”

The last question was for Dr Christiansen. How difficult is it to obtain genetic testing for HAE with normal C1 inhibitor levels?

Dr Christiansen described the availability of genetic testing in their center as a luxury. They have their own laboratory and can also send it out to others. But you have to be able to access a lab and pay for the test. For some, we know it can be a big deal to have the blood samples taken, she said.

Tony concluded the discussion by reminding the Member Organization leaders present that this valuable information could help raise awareness and knowledge, and encouraged them to work with their physicians to ensure people with HAE with normal C1 inhibitor are well managed.