Acquired C1 Esterase Inhibitor Deficiency

The complement system was first described in the late 19th century as the property of fresh serum to cause in vitro cell death after agglutination. It represents the oldest identified component of the immune system. The complement system consists of a series of about 20 different serum proteins that are part of the body's first-line, innate immune defenses (Figure 1). As such, the complement system is a triggered cascade of highly amplified proteolytic reactions ultimately leading to enhanced adherence of offending microorganisms, stimulation of more effective inflammation and phagocytosis, and direct lysis of the offending cells. The complement system is divided into two pathways on the basis of the trigger of the complement cascade. The classic pathway is activated when C1 binds to the Fc fragment of IgM or IgG in immune complexes. The inactive C1 molecule has three subunitsC1q, C1r, and C1sthat are held together by ionic calcium. The C1q component binds to immunoglobulin in the immune complex. With the binding of C1q, C1r undergoes enzymatic cleavage of its two subunits, exposing active proteolytic sites. The activated proteolytic site on C1r cleaves the C1s peptide, exposing its active enzymatic site. In turn, activated C1s acts as a protease for both C4 and C2. With the activation of C4 and C2 into C4b,2a complex, the C3 convertase enzyme is created (Figure 1). The activation of the alternate complement pathway is somewhat less clear. It involves the activation of C3 by a C3-convertase complex consisting of C3b,Bb. Under normal circumstances, low levels of turnover of C3 to C3b take place. During inflammation, low levels of C3b bind factor B, which then undergoes enzymatic cleavage by factor D to generate C3b, Bb. This in turn acts as a potent C3 convertase, amplifying the complement cascade. Therefore, successful generation of a C3-convertase enzyme complex is central to the process of complement activation by either pathway. Figure 1. Classic diagram of the complement cascade. C1 esterase inhibitor is a serum 2-globulin molecule and a member of the serpin family of protease inhibitors. It is encoded on chromosome 11 as a 17 000-base pair gene interrupted by at least seven introns. It is translated as a single-chain glycoprotein (2-globulin) containing 478 amino acid residues with a molecular weight of 105 kDa (1). The physiologic function of this hepatocyte-produced protein is inhibition of the catalytic subunits of the first component of the classic complement pathway (C1r and C1s), as well as inhibition of the function of kallikrein, plasmin, and coagulation factors XIa and XIIa. Because there are two esterase sites in C1r and C1s, each molecule of C1 binds four molecules of C1 esterase inhibitor. The binding of C1 esterase inhibitor to C1r results in loss of detectable C1r antigen activity with assay antisera. The measurement of C1r levels is therefore used to clinically follow C1 activation or inactivation. In the absence of C1 esterase inhibitor activity, activated C1 and plasmin generate activated C2 kinin (Figure 2). Activated C2 kinin is thought to be the mediator of the angioedema observed in patients with C1 esterase inhibitor deficiency. Figure 2. The mechanism of angioedema caused by C1 esterase deficiency. As a distinct entity, the clinical syndrome caused by C1 esterase inhibitor deficiency was described in 1881 (2); it was linked with C1 esterase inhibitor deficiency in 1963 (3), and an acquired form of the disease was described in 1972 (1, 4). 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 a typical autosomal dominant type of inheritance. The acquired form primarily affects adult or elderly patients with no family history for this disease. These two forms can be distinguished by measurement of serum C1q: Levels of C1q are normal in the inherited form of C1 esterase inhibitor deficiency and are decreased in the acquired form. This distinction between the two forms of C1 esterase inhibitor deficiency stems from the observation that the rate of catabolism of C1 esterase inhibitor and C1q is markedly elevated in patients with the acquired form of the disease. In the acquired form, in the setting of lymphoproliferative disorders, the large numbers of idiotype-anti-idiotype immune complexes consume the available C1q molecules, which in turn consume large amounts of C1 esterase inhibitor, resulting in quantitative and functional deficiency of the C1 esterase inhibitor. A distinct subtype of acquired C1 esterase inhibitor deficiency related to autoantibodies directed specifically at the C1 esterase inhibitor molecules has been described (2). C1q is consumed and the inhibitor activity is decreased despite normal C1 esterase inhibitor antigen levels. In the inherited form of C1 esterase inhibitor deficiency, the defect is in synthesis of the C1 esterase inhibitor protein. It may be produced in very small quantities (subtype A or 1, which accounts for 85% of all cases), or it may be produced in normal quantities but with functional impairment of the protein (subtype B or 2, which accounts for 15% of cases). In either form, C1 activation proceeds unabated, resulting in normal levels of C1q. In both the acquired and inherited forms of C1 esterase inhibitor deficiency, levels of C2 and C4 are decreased because of the uncontrolled activity of C1s. On these basis of observations, in patients with the corresponding clinical syndrome, acquired C1 esterase inhibitor deficiency is diagnosed by laboratory evidence of decreased C1q, C2, and C4 levels. Normal levels of C1q along with decreased levels of C2 and C4 suggest the diagnosis of inherited C1 esterase inhibitor deficiency. The major focus of this discussion is the acquired form of C1 esterase inhibitor deficiency. As mentioned above, this type manifests itself in two forms, one associated with lymphoproliferative disorders and the other with specific autoantibodies directed against the C1 esterase inhibitor molecule (6). Although it is a rare disorder, acquired C1 esterase inhibitor deficiency has been described in diverse clinical scenarios, including HIV (7), multiple myeloma (8), Waldenstrom macroglobulinemia (9, 10), gastric carcinoma (11), B-cell lymphoma (12, 13), rectal adenocarcinoma (14), breast carcinoma (15), chronic lymphocytic leukemia (16), systemic lupus (17), Churg-Strauss vasculitis (18), acute hepatitis B (19), plane xanthomatosis (20), and Echinococcus granulosus infection (21). In addition, acquired C1 esterase inhibitor deficiency has been reported in a patient with myelofibrosis (22) and a patient with Helicobacter pylori infection (23). Most reports represent small series or single case reports. We present the largest case series of acquired C1 esterase inhibitor deficiency published to date. This discussion includes a description of two typical patients with acquired C1 esterase inhibitor deficiency, a summary of our experience, and a review of the available literature on this topic. Methods After obtaining approval by the institutional review board, we searched the Mayo Clinic medical record computerized diagnosis database for cases of angioedema and acquired C1 esterase inhibitor deficiency. A period of 28 years was reviewed. The search revealed 4439 cases of angioedema; only 28 cases were clinically suspected of being due to acquired C1 esterase inhibitor deficiency. After careful review, only 22 cases contained the appropriate supporting data for the diagnosis of acquired C1 esterase inhibitor deficiency. To review the available published literature on acquired C1 esterase inhibitor deficiency, we searched the MEDLINE database. All available published articles were reviewed and included in the manuscript. Clinical Cases Case 1 Mr. O. is a 44-year-old man with no significant medical history who presented with acute-onset swelling in his right hand and foot. He had no associated pain or pruritus in these areas, nor could he recall any antecedent trauma. The swelling resolved over 24 to 36 hours. During that time, Mr. O. took some antihistamines, which may have contributed to the resolution. Ten months later, the patient awoke with scrotal and lower abdominal swelling. Again, he recalled no antecedent trauma and had no pain or pruritus associated with the edema. The patient applied cold packs to the affected areas, and the symptoms resolved over 3 to 4 days. The third episode occurred 4 months later. This time, facial swelling gradually increased over 2 to 3 days. The patient was seen by an allergist and received corticosteroids and antihistamines (fexofenadine), with rapid resolution of symptoms. A month later, Mr. O. had yet another episode of scrotal and lower abdominal swelling. This episode spontaneously resolved after 24 hours. Work-up during that time demonstrated an undetectable level of C4, a normal C3 level, and low C1 esterase inhibitor activity. C1q levels were also low, suggesting acquired C1 esterase inhibitor deficiency. Appropriate testing yielded evidence of a chronic B-cell lymphoproliferative disorder. Flow cytometry analysis identified a small population of monoclonal B cells in the peripheral blood. Bone marrow biopsy demonstrated about 10% involvement of the bone marrow by small lymphocytes (monoclonal B lymphocytes). The patient began therapy with danazol, 200 mg twice daily, for recurrent angioedema. No therapy was initiated for the B-cell lymphoproliferative disorder. While receiving danazol, the patient was free of recurrent angioedema but developed a skin rash. The rash was thought to be related to danazol therapy, and the regimen was changed to stanozolol, 2 mg three times daily. At 1 month of follow-up, the patient had not had any more episodes of rash or angioedema. Mr. O. remained symptom-free for the next 11 months, at which time he noted mildly enlarged cervical lymph nodes. Evaluation at that time de