Clinical Pearls & Morning Reports
Published March 18, 2020
In the past, patients with hereditary angioedema often had anxiety, depression, and disruption of work, school, and daily life. An improved understanding of the pathophysiology of hereditary angioedema and classification of phenotypes has driven the investigation of new and targeted therapies. Read the NEJM Review Article here.
Q: What causes hereditary angioedema?
A: The fundamental abnormality in hereditary angioedema types I and II is a deficiency of functional C1 inhibitor (due to a mutation in SERPING1), which regulates multiple proteases involved in the complement, contact-system, coagulation, and fibrinolytic pathways. Functional C1 inhibitor levels in hereditary angioedema with C1 inhibitor deficiency are generally 5 to 30% of the normal level, despite the presence of one normal gene. In 2000, hereditary angioedema with normal C1 inhibitor levels was described, for which molecular mechanisms are emerging. The clinical presentation is phenotypically similar to that of hereditary angioedema with C1 inhibitor deficiency, with prolonged attacks of cutaneous and submucosal swelling (lasting for approximately 2 to 5 days).
Q: What peptide is the mediator of swelling in hereditary angioedema with C1 inhibitor deficiency?
A: In hereditary angioedema with C1 inhibitor deficiency, activation of the plasma contact system generates bradykinin, which transduces its biologic effect through the engagement of G protein–coupled receptors. The bradykinin B2 receptor is constitutively expressed on endothelial cells and is considered to be principally responsible for the active transfer of fluid into localized tissues, with resultant angioedema.
A: The most important step in making a diagnosis of hereditary angioedema with C1 inhibitor deficiency is to maintain a high index of suspicion. Recurrent attacks of cutaneous angioedema (asymmetric, nonpruritic, disfiguring, and nonpitting) without urticaria or spontaneously remitting, severe abdominal symptoms (pain and swelling) or both should alert the clinician to consider hereditary angioedema. Hereditary angioedema with C1 inhibitor deficiency typically develops in childhood (mean age at onset, 8 to 12 years), rarely occurs before 1 year of age, and usually worsens during puberty. Submucosal angioedema of the intestine can mimic an acute abdomen, resulting in unnecessary surgery. Patients frequently report a variety of prodromal symptoms before the onset of an attack, including a distinctive, nonpruritic, serpiginous rash, erythema marginatum, in approximately one third of patients. Although erythema marginatum is the most specific prodrome in hereditary angioedema, its presence has been associated with diagnostic delay, presumably because of confusion with urticaria. Tingling, fatigue, asthenia, and discomfort at the site of emerging swelling have also been reported as prodromal symptoms.
A: In the past, antifibrinolytic agents (tranexamic acid or epsilon aminocaproic acid) and attenuated androgens such as danazol were the primary options for short- and long-term prophylactic care. Although these treatments are effective, outcomes have fallen far short of the goal of normalizing patients’ lives, and there is a risk of serious side effects. At present, these agents are considered second-line therapies. Until 2009, there were no FDA-approved therapies for attacks of angioedema. In the past decade, several on-demand treatments have been approved. A major advance in prophylactic care for hereditary angioedema has been the approval of subcutaneous treatments, including plasma-derived C1 inhibitor and lanadelumab, a human monoclonal inhibitor of plasma kallikrein, in both cases circumventing the requirement for intravenous access and showing improved efficacy.