The "neurotic" edema: the parent disease and its offspring.

Fremeaux-Bacchi et al. (1), in their study of hereditary angioedema, stand on the shoulders of a research lineage spanning well over a century. A rare disease, hereditary angioedema has been an important “experiment of nature,” allowing us to learn more about the action of plasma proteases and the mechanisms of edema. This disease made its debut in clinical medical history in 1882, when Quincke described a patient with recurrent attacks of circumscribed, nonsymmetrical swelling of the deep cutaneous tissues of the hands and feet (2). He noted that the patient had attacks of abdominal pain, which, he hypothesized, represented swelling of the gastrointestinal mucosa. Osler followed with a report on a family with angioedema (3). Documenting the syndrome’s occurrence in each of five generations in this family, he emphasized the hereditary nature of the disease, publishing a family tree that showed what we would now call autosomal-dominant mendelian inheritance. Subsequent physicians established that swelling attacks generally involve the gastrointestinal tract and other mucosal surfaces as well as the periphery, added severe abdominal pain to the list of presenting symptoms, and noted that swelling attacks could affect the pharynx (4). In most published series, about 25% of patients eventually died when severe attacks affected the pharynx. We can trace modern understanding of hereditary angioedema, distinguished by inquiry into the molecular basis of the disease, to 1962. In that year, Landerman et al. (5) observed that, on dilution, a hereditary angioedema patient’s plasma generates a factor that increases capillary permeability when injected in vivo. They hypothesized that patients were deficient in an inhibitor of this permeability factor. Believing kallikrein activation to be a likely cause of the capillary permeability, they suggested that the permeability factor was activated kallikrein, a protein in the kinin-generating sequence. One year later, Donaldson and Evans reported that patients with hereditary angioedema exhibit low levels of a complement regulatory protein, the C1 inhibitor (6). We now know that C1 inhibitor, a serine protease inhibitor or serpin, controls the function of many protease enzymes in plasma, including that of two subunits of C1 (C1r and C1s), mannan-binding lectin–associated proteases, activated Hageman factor and its activation fragments, factor XI of the intrinsic clotting cascade, plasmin of the fibrinolytic cascade, and kallikrein of the kinin-generating system (6). The C1 inhibitor presents a ‘bait’ sequence to the enzyme to be inhibited. When the proteolytic enzyme cleaves the bait sequence site on the C1 inhibitor, a remarkable rearrangement of the molecule occurs. The C1 inhibitor now has exposed a reactive site, which binds in a covalent manner to the active enzymatic site on the protein. Currently, it is believed that activation of the kiningenerating pathway with uncontrolled formation of bradykinin causes most of the features of this intermittent swelling disorder. In both heterozygous and homozygous C1 inhibitor– deficient mice, excessive edema exists at baseline and is further induced by activation of the kiningenerating pathway (7). Both a plasma kallikrein inhibitor and a bradykinin type 2 receptor antagonist prevent edema. Over the years, research has defined the nature of the genetic defect giving rise to hereditary angioedema, and we have clarified that this autosomal-dominant disease is manifest in heterozygous patients with one abnormal C1 inhibitor gene (8). A patient with homozygous C1 inhibitor deficiency has never been observed. The mutated gene contains either stop codons or large deletions leading to no protein secretion in 85% of patients, or point mutations leading to abnormally functioning protein in others. Since the protein is used up as it functions, one normal gene does not ensure sufficient production of the C1 inhibitor to prevent swelling attacks (7,8). For this condition, methylated attenuated androgens are useful (9). Danazol, the androgen studied most extensively, appears to increase synthesis of C1 inhibitor by the normal gene and corrects much of the biochemical abnormality (10). Research in the 1970s led to a further understanding that hereditary angioedema is not the only disease with low C1 inhibitor function. In 1972, Caldwell and colleagues reported a lymphosarcoma patient whose tumor was associated with destruction of C1 inhibitor activity and whose clinical presentation was indistinguishable from hereditary angioedema (11). Further analysis revealed a complement pattern that became the hallmark of acquired C1 inhibitor deficiency: a low C1 titer, not usually seen in hereditary angioedema, coupled with low C1 inhibitor activity, and low C4 and C2 levels, as seen in the inherited disease. The authors described an additional patient with lymphosarcoma, who had a similar complement profile but without symptoms of angioedema. Both these patients had a circulating 7S immunoglobulin (Ig) Am J Med. 2002;113:249 –251. From the Department of Pediatrics, Children’s Health Center, Duke University Medical Center, Durham, North Carolina.