“I know that the number of men and women with HAE is about equal. Are the frequency of attacks equal between the sexes?”

Jun 27, 2016
Dr. C:We thank our reader for this interesting question. Certainly for HAE C1inh the expression of disease is equal between men and women reflecting the fully penetrant, autosomal dominant pattern of inheritance for HAE types I and II. Our reader’s question explores whether differences between men and women could affect the severity of disease. We do know that changes in estrogen exposure both exogenous, (birth control pills or estrogen replacement), or naturally occurring (menarche and pregnancy) can influence attack frequency and severity. Could this translate into a risk of more severe disease overall for women? A report by Konrad Bork in 2006 provides support for this suspicion. He chronicled 221 patients with 131,110 edema episodes. On average, women were found to have a more severe course of HAE than men. He also described that early onset of swelling was linked with more severe disease—an outcome that Dr. Z and I recently reported data on from our patient registry.
The story is even more biased for HAE patients with normal C1inh. While the inheritance remains autosomal dominant in HAEnlC1inh there is incomplete penetrance. Women are affected at much greater rates than men with regard to disease expression. Men can be obligate carriers (meaning they can pass it on to their offspring) but ”silent” with respect to experiencing any attacks of swelling. Within the category of HAEnlC1inh the risk of estrogen enhancing disease severity is higher for patients with the factor XII mutation.
We need to remember that for an individual, either man or woman, that HAE is not a static disease. Severity can be affected by multiple non-hormonal factors such as trauma, concurrent illness or stress driving the frequency of swelling at different points in the life of an individual. In general however the available data would support a disproportionate burden of disease for women. Marc, can you provide some more insight on what is known about the severity differences between men and women for our readers?


Dr R:In HAE Type 1 and 2, we expect equal numbers of affected men and women due to the genetic inheritance pattern. A large German study of HAE demonstrated that, on average, women with HAE due to C1INH deficiency have more frequent angioedema attacks than men (24 vs. 20 attacks per year). Recent studies have also shown that women have more emergency department visits and hospitalizations for HAE symptoms than men, which suggests (but doesn’t prove) that HAE attacks may on average be more severe in females than in males. This apparent higher overall rate of symptoms in women is supported by additional research showing that estrogen tends to activate the contact (kallikrein-bradykinin) system, resulting in higher levels of bradykinin production. Now it’s important to note that these large studies only show averages across large populations, so clearly with the huge variability in HAE, there are individual men that have very frequent and severe angioedema symptoms and women who have fewer and milder attacks. This can be a case where ‘statistics are meaningless to the individual’, i.e. not everyone follows the trends seen in large research studies. For HAE with normal C1INH (Type 3), the data looks much different as this is a condition that is almost exclusively diagnosed in women and therefor women clearly have a greater burden of attacks compared to men. There are a few reports of HAE with normal C1INH in men with frequent angioedema symptoms, so some very rare ‘exceptions to the rule’. But this is predominantly a female condition due to the fact that higher estrogen levels appear required to ‘activate’ the angioedema symptoms in the vast majority of cases.


Dr C: Thank you Marc. Bruce, I think it would be of interest to discuss some of the “home grown” data that we have been looking at from the HAEA. Can you share our experience regarding severity of disease between women and men?


Dr Z:We looked at information from almost 650 HAE-C1INH patients who are members of the US HAEA. We saw no evidence that there was any difference between men and women in the age that they first began to swell. In contrast, men reported an average (median) of just over 13 attacks per year while women reported 24 attacks per year. We’re still trying to understand the consistent increase in attacks in women that have been seen across a number of studies. I would agree that estrogen may increase bradykinin generation. There’s also evidence that they may decrease the degradation of bradykinin as well as influence the number of bradykinin receptors. The impact of pregnancy on attacks is the most puzzling of all. While women “tend” to have more attacks while pregnant, this is highly variable – even in the same woman during separate pregnancies! Clearly, we have a lot to learn.


Dr C:Thank you Bruce and Marc. I agree—we have much more to learn. I hope that this information was of interest to our reader and followers with HAE. The good news is that the severity differences discussed between men and women may one day be of “historic interest”. With the promising new therapies on the horizon for HAE hopefully all can look forward to a future that is free from swelling. We look forward to hearing from you and our next QOTW.

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