QOTW – “Any idea as to when a test for bradykinin may be available to help finally diagnose HAE nl C1 INH?”

Apr 11, 2016

Dr. C: Happy Income Tax Time to all of our readers—may you all look forward to refunds. This question introduces what has been an ongoing problem for patients with HAE-nl-C1INH. With the exception of the factor XII mutation we have no biologic marker. The experience with drugs such as Kalbitor and Firazyr would support that the swelling is mediated by bradykinin as is the case for patients with HAE I and II. The lack of a confirmatory tests however has hampered both our ability to accurately diagnose patients and obtain appropriate therapy. Welcome back Marc—would you like to provide some insight as to why this is taking so long and what we can realistically expect?

Dr R: Bradykinin is a difficult molecule to measure reliably as the levels can be greatly influenced by a number of factors: tissue trauma from the blood draw, the type of collection tubes used, temperature, processing variability, etc. It’s also a molecule that’s degraded very rapidly (within seconds) unless a cocktail of stabilizing inhibitors are used in the lab tubes for blood collection. All of these factors add up to a very challenging test that’s highly susceptible to error and variability. Due to these obstacles, researchers have continued to investigate other lab tests or biomarkers that would be more feasible and more accurate for use in the clinical settings when bradykinin-mediated angioedema is suspected but C1INH function is normal. These include looking “upstream” at things such as kallikrein activity and “downstream” at measurements of more stable metabolites or by-products of bradykinin production, all of which could identify excessive contact system activation and ultimately bradykinin production. None of these tests are ready for prime time yet as these assays need to be studied in relatively large groups of people with various subtypes of angioedema as well as people without angioedema so that we can be confident they accurately identify or classify a bradykinin-mediated swelling condition. This data is being collected at various research centers, including the Angioedema Center at UCSD, with the goal of having a useful lab test within the next year or two. However it’s hard to predict exactly how quickly this will happen until we have the study data in hand.
Dr. C: Thank you Marc. Bruce, I know that you are planning to start assays for bradykinin at the angioedema center for our research protocol. Could you describe for our reader what assays are currently available and how you see them being potentially adopted into clinical practice?

Dr Z: Let me suggest that measurement of bradykinin would probably not be our preferred choice for a test to diagnose HAE-nl-C1INH as it would likely only be abnormal during an attack but not between attacks. On the other hand, detecting increased bradykinin during attacks would allow us to better segregate patients into differing categories and this would be useful for additional studies to develop more useful tests. Ultimately, we want to have either a genetic diagnostic test or else a robust surrogate marker for the disease. The F12 mutation has proven very useful to diagnosis a relatively small subgroup of patients with HAE-nl-C1INH. Many of us suspect that the HAE-nl-C1INH patients without a F12 mutation (now referred to as HAE-unknown) may represent a combination of different mutations, making the genetic analysis more complicated. In addition, we have no idea whether patients who appear to have bradykinin-mediated angioedema without a family history or a F12 mutation are distinct from the HAE-unknown patients. We are taking a multi-pronged approach to dealing with these questions at the Angioedema Center. Having patients get evaluated at the Center and give blood for us to study is critically important for our ability to make progress in this area. Although I can’t answer your question about which assays might be adopted into clinical practice, I do think that research breakthroughs will be quickly translated into clinical care.

Dr C: Thank you Bruce and Marc. I hope that our discussion was helpful for our reader and followers with HAE. We look forward to hearing from you and our next “Question of the Week”.

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