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C1 Esterase Inhibitor

Hereditary angioedema is caused by a deficiency or dysfunction of C1 inhibitor. C1 esterase inhibitor is a serum alpha-2 globulin and a member of the serpin family of protease inhibitors that is synthesized by the liver.  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 esterase inhibitor results in the inappropriate activation of C1 and generation of C2 kinin, 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.

Reference range for C1 esterase inhibitor antigen is 18–40 mg/dL.

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.

Reference range for C1 esterase inhibitor function is >41%.

Patients with the acquired form of C1 esterase inhibitor deficiency produce immune complexes that consume large amounts of C1q and C1 esterase inhibitor, resulting in quantitative and functional deficiency of the C1 esterase inhibitor and C1q. 

Detection of the acquired form of C1 esterase inhibitor requires measurement of C1q antigen level. 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 hereditary angioedema will have low C2 and C4 levels due to C1 activation and complement consumption. The following table differentiates acquired and hereditary C1 esterase deficiencies. 

Specimen requirement is one lavender (EDTA) tube of blood.