Hereditary angioedema (HAE) is an uncommon disease characterized by recurrent episodes of ill-defined, non-pitting, deep seated skin and mucosal swellings. Skin swellings most frequently involve the limbs followed by face, genitals and lips. In addition, patients may experience recurrent episodes of abdominal pain. Laryngeal edema is a potentially life-threatening manifestation of HAE. Each episode of angioedema often lasts for 3-5 days. Though the episodes can be spontaneous in onset, many a times, these are heralded by physical trauma, mental stress, infections and dental or other surgical procedures.
The prevalence of HAE is approximately 1 in 10,000 to 1 in 50,000 people.
HAE is a genetic disease and it runs in families. Approximately 80% patients have a family history of similar illness. However, in approximately 20% patients the defect is de novo and there is no suggestive family history of similar illness. There is a 50% risk of having a child with HAE if one of the parents is affected with this condition.
The generation of bradykinin in the blood is normally inhibited by C1-esterase inhibitor or simply called C1-inhibitor (C1-INH). There are three types of HAE. Type I and type II HAE are now classified as C1-INH-HAE and are caused by mutation in the SERPING1 gene. Type I constitutes 85% of C1-INH-HAE cases. In type I HAE, both levels and function of C1-INH are low; whereas in type II, the C1-INH is dysfunctional, and therefore, the levels are normal to elevated, however, function is low. Type III HAE, now classified as nl-C1-INH-HAE, is not characterized by deficiency or dysfunction of C1-INH. These patients have rare mutations in factor XII, angiopoietin, kininogen, plasminogen, myoferlin or heparan sulfate 3-O-sulfotransferase 6 gene. The diagnosis of nl-C1-INH-HAE can only be established by doing the genetic testing.
Diagnosis of HAE should be considered in any patient who presents with angioedema in the absence of wheals (Wheals are intensely pruritic, superficial, well-defined swelling of skin that usually last for few hours).
Angioedema associated with wheals is commonly encountered in patients having acute or chronic urticaria or anaphylaxis, and the chief mediator for its development is histamine. Angioedema not associated with wheals is a different entity, mediated by bradykinin. HAE is the most important entity in this category. Instead of urticaria, these patients often have tingling, numbness, pain and formation of serpiginous to annular, non-pruritic patches on skin (also known as erythema marginatum). Erythema marginatum may be seen in approximately 50% of all patients with HAE and may be confused with an urticarial rash.
C4, C1-INH levels, C1-INH function should be tested in all patients with suspected HAE. The diagnosis of patients with type 1 HAE depends on demonstration of low C4 and low C1-INH levels while patients with type 2 HAE have normal to high levels of C1-INH and low C1-INH function. The diagnosis of type 3 (nl-C1-INH-HAE) depends on a high index of suspicion and needs to be confirmed with genetic testing.
The management of HAE is divided into the treatment of acute attack, short-term prophylaxis and long-term prophylaxis.
Treatment of acute attacks comprises of plasma derived or recombinant C1-inhibitor, kallikrein antagonists (Ecallantide) and bradykinin B2 receptor antagonists (Icatibant). Because of non-availability of these products in India, most patients are given fresh frozen plasma for the treatment of acute attacks.
Short-term prophylaxis is used when there is an anticipated risk of an attack of angioedema such as during dental procedures and any other major surgery. Plasma derived or recombinant C1-inhibitor and bradykinin B2 receptor antagonists (Icatibant) are the mainstay of therapy for these situations. However, because of non-availability of these products in India, most patients are given a combination of attenuated androgens (stanozolol or danazol) and fresh frozen plasma.
Long-term prophylaxis is given to patients with HAE who have frequent attacks of angioedema leading to an impaired quality of life and risk of life-threatening laryngeal attacks. Plasma derived C1-inhibitor and kallikrein antagonists (Lanadelumab) are the mainstay of therapy for long-term prophylaxis. In India, tranexamic acid and attenuated androgens (stanozolol or danazol) are used as prophylactic treatment for most patients with HAE.