Clinical Information

C1 esterase inhibitor (C1-INH) is a multispecific protease inhibitor that is present in normal human plasma and serum and regulates enzymes of the complement, coagulation, fibrinolytic, and kinin-forming systems. The enzymes (proteases) regulated by this protein include the C1r and C1s subunits of the activated first component of complement (the C1qrs complex), activated Hageman factor (factor XIa), kallikrein (Fletcher factor), and plasmin.

A deficiency of functionally active C1-INH may lead to life-threatening angioedema. Two major forms of C1- INH deficiency have been reported: the congenital form, termed hereditary angioedema (HAE), and the acquired form, which is associated with a variety of diseases, acquired angioedema (AAE).

In HAE, there is insufficient C1-INH to negatively regulate bradykinin release and stop angioedema attacks from occurring. The mechanism of HAE attacks is distinct from an allergic angioedema as it is not mediated by histamine release via mast cell activation. Therefore, HAE patients are unresponsive to antihistamines or corticosteroids.

There are 2 main types of HAE that are attributed to C1-INH deficiency (Type I) or dysfunction (Type II), resulting in C1-INH activity ranging from less than 20% to 50% of normal. Type I HAEs, representing approximately 85% of patients, are associated with low circulating concentrations of C1-INH, leading to a concomitant decrease in C1-INH function. In Type II HAEs, normal or elevated concentrations of functionally inactive C1-INH are produced. The relative proportion of Type I and Type II HAE may differ based on geographical location.

A third HAE subtype with unknown prevalence termed "HAE with normal C1-INH" has been described. Although poorly characterized, a minority of these patients is known to harbor a variant in Factor XII; the disease origin for the remainder of patients remains unknown. Factor XII is the zymogen form of Factor XIIa and plays a key role in bradykinin production as part of the contact system.

Angioedema due to C1-INH deficiency can also be acquired during adulthood in the fifth decade of life or later. The prevalence of AAE is extremely low and is estimated at 10% of HAE. AAE is frequently associated with monoclonal gammopathies or lymphoproliferative disease as well as different types of cancer and autoimmune diseases. AAE may be caused by development of anti-C1-INH autoantibodies, which act to reduce the functional activity or increase the catabolism of C1-INH.

For patients exhibiting symptoms associated with HAE, evaluation of pertinent family history in combination with laboratory results for C1-INH function and concentration, C4 concentration, and C1q concentration can assist in HAE diagnosis and determination of HAE type. Identification of low C1-INH function and low C4 concentration support the diagnosis of HAE and was found to have 98% specificity towards C1-INH deficiency and a negative predictive value of 95%. C4 is decreased owing to excessive consumption through the classical pathway in the absence of inhibition by C1-INH. Due to low disease prevalence, false-positive results are common and therefore, repeated testing is recommended to confirm findings.