C1 Esterase Inhibitor
Hereditary angioedema is caused by a deficiency or dysfunction of C1 esterase inhibitor (C1-INH). C1 esterase inhibitor is a serum alpha-2 globulin and a member of the serpin family of protease inhibitors that is primarily synthesized by the liver. Mononuclear cells and fibroblasts also synthesize and secrete it. C1 esterase inhibitor is an important regulator of the complement, coagulation, and kallikrein–kinin cascades. Its physiologic function is inhibition of the catalytic subunits of the first component of the classic complement pathway (C1r and C1s). Deficiency of C1-INH results in the inappropriate activation of C1 and generation of C2, uncontrolled generation of plasma kallikrein and consequent proteolysis of high molecular weight kininogen. Excessive bradykinin is produced, which causes vasodilation, vascular leakage, and subsequent angioedema and pain. Patients experience recurrent swelling of the subcutaneous tissues of the hands, feet, face, and abdomen and the submucosal tissues of the larynx and genitourinary tract. Swelling of the larynx can be life-threatening because of the risk of asphyxiation.
There are two forms of C1 esterase inhibitor deficiency. The inherited form is usually detected in the first or second decade of life and has an autosomal dominant pattern of inheritance. The acquired form primarily affects adult or elderly patients with autoimmune or lymphoproliferative disorders.
In the inherited form of C1 esterase inhibitor deficiency, there is either a quantitative or qualitative defect in the synthesis of the C1 esterase inhibitor protein. The more common form of hereditary angioedema (85% of cases) is due to an absolute decrease in the synthesis of the C1esterase inhibitor. C1-INH protein and functional activity are both decreased.
The less common form of hereditary angioedema (15% of cases) is due to production of normal quantities of a functionally deficient protein. Detection of this form of the disease requires a functional assay of C1 esterase inhibitor activity. These patients have normal or increased levels of C1 esterase inhibitor antigen, but decreased levels of functional C1 esterase inhibitor activity.
There are no clinical differences between the two types of inherited C1-INH deficiency, but it is important to remember that the antigen test for C1-INH is insufficient to define all cases of inherited C1-INH deficiency. In either case, C2 and C4 levels are usually reduced below the lower limit of normal between attacks and are always reduced during attacks, due to uncontrolled cleavage by C1s.
Acquired C1-INH deficiency typically presents in the fourth decade of life or later and often has an underlying lymphoproliferative or autoimmune disorder. Patients with an acquired deficiency produce immune complexes that consume large amounts of C1q and C1 esterase inhibitor, resulting in quantitative and functional deficiency of both. C1q is the measurable component of the C1 complex, C1qrs. This deficiency is not seen in patients with hereditary angioedema. C1-INH antigen may be low or normal in patients with acquired deficiency.
Acquired C1-INH deficiency can be distinguished from inherited deficiency by measurement of C1q and C4 complement levels. Patients with the hereditary disease have normal levels of C1q, while those with the acquired form have low levels. Patients with current attacks of all forms of angioedema will have low C2 and C4 levels due to C1 activation and complement consumption.
Differentiation of Acquire and Hereditary Deficiencies
|
Type of Deficiency |
C1q Levels |
C4 Levels |
|
Inherited |
Normal |
Decreased |
|
Acquired |
Decreased |
Decreased |
Reference range for C1 esterase inhibitor antigen is 18–40 mg/dL.
Reference range for C1 esterase inhibitor function is >41%.
Reference range for C1q is 12-22 mg/dL.
Reference range for C4 is 14-40 mg/dL.
Specimen requirement is one lavender (EDTA) tube of blood.
