Acquired C1-inhibitor deficiency and lymphoproliferative disorders: a tight relationship

Angioedema due to the acquired deficiency of C1-inhibitor is a rare disease known as acquired angioedema (AAE), which was first described in a patient with high-grade lymphoma and is frequently associated with lymphoproliferative diseases, including expansion of B cell clones producing anti-C1-INH autoantibodies, monoclonal gammopathy of uncertain significance (MGUS) and non-Hodgkin lymphoma (NHL). AAE is clinically similar to hereditary angioedema (HAE), and is characterized by recurrent episodes of sub-cutaneous and sub-mucosal edema. It may affect the face, tongue, extremities, trunk and genitals. The involvement of the gastrointestinal tract causes bowel sub-occlusion with severe pain, vomiting and diarrhea, whereas laryngeal edema can be life-threatening. Unlike those with HAE, AAE patients usually have late-onset symptoms, do not have a family history of angioedema and present variable response to treatment due to the hyper-catabolism of C1-inhibitor. Reduced C1-inhibitor function leads to activation of the classic complement pathway with its consumption and activation of the contact system leading to the generation of the vasoactive peptide bradykinin, which increases vascular permeability and induces angioedema. Lymphoprolipherative diseases and AAE are tightly linked with either angioedema or limphoprolyferation being the first symptom. Experimental data indicate that neoplastic tissue and/or anti-C1-inhibitor antibodies induce C1-inhibitor consumption, and this is further supported by the observation that cytotoxic treatment of the lymphoproliferative diseases associated with AAE variably reverses the complement impairment and leads to a clinical improvement in angioedema symptoms.