Clinical Pearls & Morning Reports
Published March 16, 2022
Hereditary angioedema with C1 inhibitor deficiency is often misdiagnosed. Read the NEJM Case Records of the Massachusetts General Hospital here.
Q: Is hereditary angioedema with C1 inhibitor deficiency a rare disease?
A: Hereditary angioedema with C1 inhibitor deficiency is a rare autosomal dominant disease that is characterized by recurrent episodes of swelling that most commonly affect the arms, legs, gastrointestinal tract, face, or larynx. Episodes are typically self-limited, but abdominal attacks may cause severe pain, nausea, and vomiting; episodes in which the throat or larynx is affected may be fatal if untreated.
Q: How do hereditary angioedema type I and II differ, and how does type I differ from acquired C1 inhibitor deficiency?
A: In hereditary angioedema type I, which accounts for approximately 85% of cases, mutations in SERPING1 result in an antigenic (quantitative) deficiency in C1 inhibitor (which is encoded by SERPING1), with decreased C1 inhibitor function. In contrast, in hereditary angioedema type II, mutations in SERPING1 that directly affect the critical functionally reactive central loop of C1 inhibitor result in an antigenically (quantitatively) normal C1 inhibitor level but decreased C1 inhibitor function. In patients with hereditary angioedema, the C1q level is normal, since the activation of complement is distal to C1q. In patients with acquired C1 inhibitor deficiency, owing to the presence of antibodies to C1 inhibitor, the C1 inhibitor–C1 inhibitor antibody complex fixes C1q and thus depletes the C1q level.
A: Heterozygous loss-of-function variants in SERPING1 account for more than 95% of cases of hereditary angioedema, and at least 700 causative variants have been reported. A family history of angioedema is absent in 20 to 25% of persons with hereditary angioedema with C1 inhibitor deficiency, in whom spontaneous new genetic mutations presumably occur.
A: The goal of on-demand treatment is to resolve symptoms as quickly as possible after the onset of swelling. On-demand medication options in the United States include a kallikrein inhibitor (ecallantide), a bradykinin B2 receptor antagonist (icatibant), a plasma-derived C1 inhibitor concentrate, and a recombinant C1 inhibitor. Long-term prophylactic treatment is appropriate for patients who do not have adequate benefit from on-demand therapy. Androgens such as danazol have been available for many years, and antifibrinolytics treat the disorder successfully but are associated with clinically significant side effects. Newer therapies that are available in the United States include intravenous plasma-derived C1 inhibitor concentrate, a subcutaneous formulation of plasma-derived C1 inhibitor concentrate, a monoclonal antibody that inhibits active plasma kallikrein (lanadelumab-flyo), and an oral kallikrein inhibitor (berotralstat). The goal of short-term prophylaxis, the third main treatment category, is to reduce the likelihood of swelling in response to anticipated events that are likely to precipitate an attack (e.g., medical or dental procedures).