Clinical Pearls & Morning Reports
Published January 3, 2024
The hallmark symptom of hereditary angioedema is localized swelling of the skin and submucosal tissues (in the face, lips, throat, hands, feet, or genitalia) that is nonpitting, nonpruritic, and not accompanied by urticaria. Read the NEJM Clinical Problem-Solving Article here.
Q: At what age does hereditary angioedema typically manifest?
A: Hereditary angioedema is a rare autosomal dominant genetic disorder. It typically develops in childhood, with a mean age of onset of 8 to 12 years, and symptoms often worsen during puberty. The disease is characterized by recurrent episodes of swelling in various parts of the body and can be severely debilitating. Triggers include emotional stress, physical trauma, infections, physical exertion, and surgery and other medical procedures.
Q: What is underlying cause of most types of hereditary angioedema?
A: The fundamental defect in most types of hereditary angioedema is deficiency of functional C1 inhibitor protein, a protease belonging to the superfamily of serine protease inhibitors (serpins). The majority of cases of hereditary angioedema are caused by either decreased levels (type I) or reduced functionality (type II) of C1 inhibitor. A deficiency or lack of C1 inhibitor results in unregulated activation of plasma proteolytic cascades that generate bradykinin, the principle vasoactive peptide responsible for swelling in hereditary angioedema. The initial molecular events in the genesis of an attack are not entirely understood, but the activation of factor XII and plasma prekallikrein are key components.
A: Swelling typically occurs suddenly. Abdominal pain can be the sole symptom in an attack of angioedema. Although the skin and bowel appear to be the most frequently involved organs, the genitalia, bladder, muscles, or joints may also be involved. Laryngeal edema occurs in approximately 0.9% of all attacks and may be life-threatening, leading to asphyxiation and death. The duration of attacks has been reported to range from a few hours to a few days, with substantial interpatient variability. Although prodromal symptoms are not always present, patients often report early signs that precede an impending attack. Up to one half of patients have a characteristic serpiginous rash, known as erythema marginatum, which is often confused for urticaria, resulting in diagnostic delay. Other reported prodromal symptoms include fatigue and transient numbness or tingling at the site of emerging swelling.
A: First-line on-demand therapies act by replacing missing or dysfunctional C1 inhibitor or by inhibiting the action of bradykinin, the main mediator of angioedema attacks; Food and Drug Administration–approved agents include human plasma–derived C1 inhibitor concentrate, recombinant human C1 inhibitor, icatibant (bradykinin B2 receptor antagonist), and ecallantide (kallikrein inhibitor). Each has been shown in randomized, controlled trials to decrease the median time to symptom relief. Preprocedural prophylaxis is recommended for patients undergoing procedures that may trigger an attack (e.g., dental surgery, endotracheal intubation, or an endoscopic procedure). For patients who have frequent attacks, long-term prophylaxis is recommended. In these patients, intravenous or subcutaneous administration of plasma-derived C1 inhibitor can be given at least twice a week. Other prophylactic therapies include danazol, lanadelumab, and berotralstat.