Angioedema is a subcutaneous extension of urticaria, resulting in deep swelling within subcutaneous sites. In contrast, urticaria results from transient extravasation of plasma into the dermis, causing a wheal characterized by tense edema with or without redness.
Angioedema can occur with generalized urticaria if the tissue swelling has indistinct borders around the eyelids and lips. In addition, when the swelling of urticaria extends to the face, hands, feet, and genitalia, the clinical manifestation may be called angioedema. As many as 50% of children who have urticaria exhibit angioedema, with swelling of the hands and feet.
Classification of angioedema
Based on the current clinical understanding of angioedema, dividing cases into the following types is useful:
Hereditary angioedema type 1 (HAE1)
Hereditary angioedema type 2 (HAE2)
Hereditary angioedema type 3 (HAE3)
Acquired angioedema type 1 (AAE1) (very rare; only a few reported cases)
Acquired angioedema type 2 (AAE2) (very rare; only a few reported cases)
Nonhistaminergic angioedema (INAE) (may occur in approximately 1 of 20 angioedema cases)
Allergic angioedema (most common form)
ACE inhibitor–induced angioedema (4-8% of cases)
Hereditary angioedema (HAE) accounts for only 0.4% of angioedema cases; however, the specific diagnostic tests and high mortality rate associated with hereditary angioedema deserve special attention.
In 1876, Milton described the first case of hereditary angioedema. Six years later, Quincke introduced the term angioneurotic edema to describe this disease. Later, Osler described the disease as episodic bouts of well-circumscribed nonpitting subepithelial edema that primarily involved the extremities, larynx, face, and abdomen.
Hereditary angioedema is an autosomal dominant disease usually associated with a positive family history of angioedema. However, numerous cases are due to a new mutation of the gene.
In approximately 80-85% of hereditary angioedema cases, serum levels of C1 inhibitor (C1INH) are decreased to approximately 30% of reference range values. In contrast, about 15% of patients with hereditary angioedema have reference range levels of antigenic, but mostly nonfunctional, C1INH. Missing or nonfunctional C1INH leads to failure in controlling the enzymatic activity of C1, resulting in lower levels of the early-acting complement components C4 and C2 because of overconsumption.
No close relationship between plasma C1INH levels and the severity of attacks has been noted. Some patients with very low C1INH levels have few attacks, whereas others with much higher levels of C1INH have much more severe disease.
HAE1 (low levels of functional C1INH) may be due to a wide range of gene mutations. In HAE2 (reference range or even increased levels of antigenic but nonfunctional C1INH), different point mutations have been described within or near the reactive center of the C1INH gene (SERPING1). (See the image below.)
The mechanism of angioedema resulting from C1-esterase inhibitor deficiency.
The structural abnormalities in the SERPING1 genes in patients with hereditary angioedema have been found to be very heterogeneous. More than 150 mutations have been reported in unrelated patients. Agostino et al have reported on the details of genetic analysis.
HAE3 is the most recently described type of hereditary angioedema. In HAE3, C1INH function and complement components are normal.
Mutations in the gene that encodes coagulation factor XII (Hageman factor) have been found in some patients with HAE3.
Essential features of HAE3 include the following:
A long history of recurrent skin swelling, attacks of abdominal pain, or episodes of upper airway obstruction
Familial occurrence, exclusively in female members of the family
No history of urticaria in the patient or other family members
Normal C1INH and C4 concentrations in the plasma
Failure to respond to antihistamines, corticosteroids, or C1INH concentrate
AAE1 is usually linked to an underlying lymphoproliferative disorder. Complement-activating factors, idiotype/anti-idiotype antibodies, or other immune complexes associated with the underlying disorder destroys the function of C1INH. The onset of angioedema can precede other symptoms of a lymphoproliferative disease; thus, exploring the possibility of underlying malignancy in cases of AAE1 is vital.
AAE2 is associated with autoantibodies that directly inhibit C1INH function. No underlying disorder is apparent. AAE1 and AAE2 are very rare in the pediatric population.
INAE angioedema is angioedema without urticaria. Patients usually do not respond to H1 blockers (antihistamines). Parasites, infections, and autoimmune diseases are not present.
The idiopathic form of angioedema may be associated with swelling, hives that persist longer than 6 weeks, or both. Thyroid dysfunction should be considered.
Allergic angioedema is characterized by swelling, hives, or both in reaction to environmental factors such as food, an insect sting or bite, cold, heat, latex, or a drug. Usually, these environmental factors provoke histamine release that leads to swelling, hives, or both.
Angioedema can also be caused by ACE inhibitors (eg, captopril, enalapril, genzapril, quinapril, ramipril) used to treat high blood pressure. Swelling may begin a few hours to years after first starting the medication.