Angioedema without wheals: a clinical update

Abstract

Angioedema without wheals (urticaria) represents a heterogeneous group of clinically indistinguishable diseases of hereditary or acquired etiology. Hereditary angioedema is a rare inherited condition leading to recurrent, sometimes life-threatening angioedema attacks in subcutaneous tissues and gastrointestinal and oropharyngeal mucosa dating back to childhood or adolescence. Most of these patients have mutations in the SERPING1 gene, causing either low C1 inhibitor production (hereditary angioedema with C1 inhibitor deficiency type I) or the production of dysfunctional C1 inhibitor (hereditary angioedema with C1 inhibitor deficiency type II). Hereditary angioedema with normal C1 inhibitor has been defined later. Although C1 inhibitor concentration and function are in the normal range, it leads to typical hereditary angioedema symptoms owing to mutations in FXII, PLG, ANGPT1, KNG1, and MYOF genes. Patients who exhibit none of these genetic mutations despite having a similar clinical presentation are classified as having unknown hereditary angioedema. Fewer than 1 in 10 patients with C1 inhibitor deficiency have acquired angioedema with C1 inhibitor deficiency. The clinical presentation is very similar to that of hereditary angioedema, making it difficult to distinguish these 2 conditions clinically. Unlike hereditary angioedema, there are no genetic mutations, and family history and symptoms tend to appear later in life. Acquired angioedema with C1 inhibitor deficiency is commonly associated with lymphoproliferative and autoimmune diseases. Angioedema attacks might start 1 year before the underlying disease in acquired angioedema with C1 inhibitor deficiency. Approximately half of the patients admitted to the hospital for acute angioedema are patients receiving angiotensin-converting enzyme (ACE) inhibitor therapy. Angioedema typically occurs on the lips, tongue, mouth, pharynx, and subglottic regions. Patients may require hospitalization and intensive care monitoring owing to airway involvement. Idiopathic histaminergic acquired angioedema may be diagnosed only when any possible causes of histaminergic angioedema are excluded (foods, drugs, animal dander, aeroallergens, insect stings, latex, and others), and the symptoms respond well to antihistamine treatment. Idiopathic nonhistaminergic acquired angioedema should be considered when all other types of recurrent angioedema have been ruled out and patients do not respond to high-dose antihistamines. The lack of a standard biochemical laboratory test for patients with idiopathic histaminergic acquired angioedema, idiopathic nonhistaminergic acquired angioedema, angiotensin-converting enzyme inhibitor-induced acquired angioedema, and hereditary angioedema with normal C1 inhibitor makes the diagnosis more challenging. Future efforts should focus on increasing awareness of all the rare types of angioedema among physicians and developing more straightforward and more accessible diagnostic methods.

FIG. 1

Classification of angioedema without urticaria (modified from reference 15). IH-AAE, Idiopathic histaminergic acquired angioedema; InH-AAE, Idiopathic non-histaminergic acquired angioedema; ACEi-AE, ACEi associated angioedema; C1-INH-AAE, Acquired AE with C1-Inh deficiency; C1-INH-HAE type I, Hereditary AE with C1-Inh deficiency; C1-INH-HAE type II, Hereditary AE with C1-Inh dysfunction; FXII-HAE, Hereditary AE with FXII Mutation; PLG-HAE, Hereditary AE with PLG Mutation; ANGPT1-HAE, Hereditary AE with ANGPT1 Mutation; KNG1-HAE, Hereditary AE with Kininogen1 Mutation; MYOF-HAE, Hereditary AE with Myoferlin Mutation; U-HAE: Hereditary AE with unknown origin.