Angioedema without wheals: a clinical update

Angioedema without wheals (urticaria) represents a heterogeneous groupof 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 andgastrointestinal 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 C1inhibitor deficiency type I) or the production of dysfunctional C1 inhibitor(hereditary angioedema with C1 inhibitor deficiency type II). Hereditaryangioedema with normal C1 inhibitor has been defined later. Although C1inhibitor 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 thesegenetic mutations despite having a similar clinical presentation are classified as having unknown hereditary angioedema. Fewer than 1 in 10 patientswith C1 inhibitor deficiency have acquired angioedema with C1 inhibitordeficiency. The clinical presentation is very similar to that of hereditaryangioedema, making it difficult to distinguish these 2 conditions clinically.Unlike hereditary angioedema, there are no genetic mutations, and familyhistory and symptoms tend to appear later in life. Acquired angioedema withC1 inhibitor deficiency is commonly associated with lymphoproliferativeand autoimmune diseases. Angioedema attacks might start 1 year before theunderlying 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) inhibitortherapy. Angioedema typically occurs on the lips, tongue, mouth, pharynx,and subglottic regions. Patients may require hospitalization and intensivecare 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 toantihistamine treatment. Idiopathic nonhistaminergic acquired angioedemashould be considered when all other types of recurrent angioedema havebeen ruled out and patients do not respond to high-dose antihistamines. Thelack of a standard biochemical laboratory test for patients with idiopathichistaminergic acquired angioedema, idiopathic nonhistaminergic acquiredangioedema, angiotensin-converting enzyme inhibitor-induced acquiredangioedema, and hereditary angioedema with normal C1 inhibitor makesthe diagnosis more challenging. Future efforts should focus on increasingawareness of all the rare types of angioedema among physicians and developing more straightforward and more accessible diagnostic methods.

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