In a paper published in Seminars in Thrombosis and Hemostasis, Petersen and colleagues presented a typical case study of a patient eventually diagnosed with hereditary angioedema.
A 21-year-old woman presented to the emergency department with acute throat swelling. She described having recurrent episodes of swelling in her extremities that typically resolved spontaneously within 3 days. These swellings were nonpruritic and were never accompanied by hives. They started in puberty and occurred around once a month. She had tried high-dose antihistamines to no avail.
The patient previously presented twice to the emergency department, both for extreme abdominal pain with nausea and vomiting. In both cases, no cause was identified. In terms of family history, her mother had similar episodes of edema with less frequency. Her grandfather died of asphyxiation at 30 years of age.
At the emergency department, the patient was given the working diagnosis of laryngeal edema and was immediately administered epinephrine, clemastine, and dexamethasone. However, the swelling in her throat persisted. She underwent laryngeal intubation to secure her airway and was admitted to the intensive care unit.
Read more about hereditary angioedema etiology
“An empirical dose of plasma-derived C1-inhibitor was administered, after which the edema swiftly resolved,” Petersen et al wrote.
The patient was prescribed a subcutaneous bradykinin B2 receptor inhibitor to be administered in case of another attack and was subsequently discharged. After a few weeks, laboratory tests confirmed the diagnosis of hereditary angioedema (HAE) type 1 due to C1-inhibitor deficiency. She was then started on prophylactic subcutaneous plasma-derived C1-inhibitor concentrate twice weekly.
In the months following her hospital admission, she occasionally experienced breakthrough attacks that responded well to the bradykinin B2 receptor inhibitors.
How Attacks Are Precipitated
This case study is a typical presentation of how HAE is diagnosed: a patient experiences occasional episodes of swelling, undergoes an acute and particularly painful episode, presents to the emergency department, and is diagnosed with HAE after an investigation.
HAE is driven by either an absolute C1-inhibitor deficiency or C1-inhibitor dysfunction. C1-inhibitors regulate a number of important pathways, such as the kallikrein-kinin system, the complement cascade, and the intrinsic coagulation system.
When factor XII is autoactivated upon contact with negatively charged surfaces, the cleavage of the zymogen prekallikrein into plasma kallikrein is induced. This chain of events subsequently drives the production of bradykinin, which plays an important role in vasodilation and the transfer of fluid to extravasated tissue.
“Bradykinin binds to the bradykinin B2 receptor expressed on endothelial cells, initiating a signaling cascade leading to increased vascular permeability through several mechanisms including the release of nitric oxide, contraction of endothelial cells, and the uncoupling of tight junctions between endothelial cells,” Petersen and colleagues wrote.
These actions cause fluid to accumulate in the mucosal tissues or the deeper layers of the skin. Angioedema attacks develop over a course of a few hours and can last up to 5 days if left untreated. In the extremities, upper airways, gastrointestinal tract, and genitals, angioedema attacks are often described as painful but rarely itchy. The most severe complication is the development of laryngeal edema, which can quickly cause asphyxiation.
“Swelling attacks can be provoked by (mild) injury, mental stress, physical exertion, menstruation, infection, or dental procedures, or develop spontaneously,” De Maat and colleagues wrote in the Journal of Thrombosis and Haemostasis.
Read more about hereditary angioedema treatment
Patients often fail to recognize the prodromal symptoms of a hereditary angioedema attack. Among the various locations where an attack can take place, the gastrointestinal tract is common—patients often describe colicky pain accompanied by diarrhea and vomiting. This was true for the patient in the above case study. Patients are sometimes subjected to unnecessary surgical procedures for fear of an acute abdomen.
Hypotension is not a typical feature of hereditary angioedema; this is because increased permeability tends to be restricted to the location of the attack. Nevertheless, attacks at multiple locations at the same time can occur. A study reported that a third of patients experience multiple, anatomically distinct attack locations simultaneously.
“[Hereditary angioedema] treatment consists of a twin-track approach, consisting of symptom relief in the case of an attack on one hand, and the overall decrease in attacks on the other hand,” Petersen and colleagues wrote.
The most common approach to an acute attack is to prescribe an on-demand treatment as early as possible. This is considered a best practice as it achieves the best treatment response. First-line on-demand therapeutic options include icatibant and ecallantide.
It should be noted that there have been numerous reports of patients who experience edema attacks but have normal C1-inhibitor activity. If the patient has a family history of these attacks, it can be classified as hereditary angioedema of unknown origin. There is some evidence that bradykinin still plays a role in these attacks as patients tend to respond well to bradykinin receptor 2 antagonists. In addition, some patients improve clinically upon the administration of C1-inhibitors, suggesting that the contact system is involved.
One of the most significant challenges when it comes to hereditary angioedema is correctly identifying the disease in the first place. The average time to diagnosis is 8.5 years. The most common misdiagnosis is a mast cell-driven disease, such as an allergic reaction. Patients often self-treat if they suspect the swelling is trauma-related or induced by an insect sting.
Petersen RS, Fijen LM, Levi M, Cohn DM. Hereditary angioedema: the clinical picture of excessive contact activation. Semin Thromb Hemost. 2022;10.1055/s-0042-1758820. doi:10.1055/s-0042-1758820
De Maat S, Hofman ZLM, Maas C. Hereditary angioedema: the plasma contact system out of control. J Thromb Haemost. 2018;16(9):1674-1685. doi:10.1111/jth.14209