NIH CONFERENCE
Hereditary Angioedema: the Clinical Syndrome and Its Management Moderator:
MICHAEL M. FRANK, M.D.;
Discussants: JEFFREY A. GELFAND, M.D.; and
JOHN P. ATKINSON, M.D.; Bethesda, Maryland
Hereditary angioedema is manifested by attacks of swelling of the extremities, face, trunk, airway, or abdominal viscera, occurring spontaneously or secondary to trauma. It is inherited as an autosomal dominant trait and is due to deficient activity of the inhibitor of the activated first component of complement. The clinical diagnosis can be confirmed by the findings of low levels of C4 or C I esterase inhibitor activity, or both. Therapy may be divided into three phases: long-term prophylaxis of attacks, short-term prophylaxis of attacks, and treatment of acute attacks. Long-term prophylaxis may be achieved with antifibrinolytic agents and androgens. Short-term prophylaxis with these agents and plasma transfusions has been successful. Specific therapy for acute attacks is not available, but good supportive care, together with a knowledge of the course of the disease, can prevent asphyxiation from airway obstruction. Before the advent of therapy, mortality was reported as high as 3 0 % .
DR. MICHAEL M. FRANK*: Recently, hereditary angioedema has received increasing attention in the medical literature because it is an important example of the socalled "experiments of nature," which include diseases that are characterized by a well-defined, circumscribed biochemical or cellular defect that provides an opportunity to define basic pathophysiologic mechanisms. Although the clinical entity has been defined for many years (1, 2), the biochemical abnormality responsible for the development of the illness has been identified only recently (3). With our greater knowledge of the pathophysiology of this disease, we realize that study of it may provide a better understanding of the normal function of several of the enzyme systems in plasma. We think of hereditary angioedema as a disease that affects not only the complement system, but also the * Head, Clinical Immunology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases. • An edited transcription of a Combined Clinical Staff Conference at the Clinical Center, Bethesda, Maryland, 9 January 1975, by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S. Department of Health, Education, and Welfare. 580
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kinin-generating and fibrinolytic systems. Most of the recent reports on hereditary angioedema have dealt with its pathophysiology. The clinical literature has pointed out the high mortality associated with the disease and the difficulty in treating attacks (4, 5). However, relatively little attention has been paid to the clinical syndrome and therapy of this condition. Thus, a clinician caring for a patient with this potentially life-threatening illness does not have one source to consult for current developments in therapy. Patients with hereditary angioedema have been treated at the Clinical Center for the past 6 years. We review here our current understanding of the disease, with special attention to the clinical manifestations that we have seen in our patients and management of the various clinical problems that may develop. The Clinical Syndrome
Dr. Jeffrey A. Gelfandf: Hereditary angioedema has a significant morbidity rate, which rises markedly when the disease is unsuspected and undiagnosed. Our patients had symptoms for an average of 21 years before hereditary angioedema was diagnosed. We report here the clinical characteristics of 30 patients with hereditary angioedema who were followed closely at the Clinical Center. For estimates of mortality, we questioned our patients about their family members. Including family members whose serum we were able to test and those with a clear clinical history, we studied a total of 72 affected persons. Of these, 10 died from the disease or its complications. Although our referral population may represent a biased sample, these figures nevertheless indicate how severe the disease may be and how late in its course it may be diagnosed. The cardinal symptoms of hereditary angioedema are edema of the extremities, face, and airway, and recurrent abdominal pain (1, 2, 4, 5); they are not mutually exclusive and may be seen in combination. We questioned our patients about the onset of their illness. Seventy-five percent remembered swelling of the extremities as a t Clinical Associate, Clinical Immunology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases.
presenting sign, 36% recalled swelling of the face or throat, and 52% recalled recurrent bouts of abdominal pain. In our series, 39% of the patients could attribute their first episode to a clearly identifiable traumatic event such as tonsillectomy, dental manipulation, or accidental trauma. This is probably a conservative estimate of the incidence of trauma in the initial presentation of the disease, as patients later learned to regard some relatively simple activities as having traumatic potential. Patients have mentioned that activities such as typing, prolonged writing, pushing a lawn mower, hammering, or even standing in place for several hours will provoke edema in the extremities involved. Activities such as sexual intercourse and horseback riding have produced edema of the genitalia in some of our patients. Age was of minimal help in making the diagnosis. Our patients range in age from 10 to 72 years. More than half of them noted the onset of their symptoms before the age of 7, and over two thirds became symptomatic before age 13 (Figure 1). This is in contrast to idiopathic angioedema in which onset generally occurs in adult life. However, our oldest patient, now 72 years old, became symptomatic after age 50. The age of onset was not significantly different between men and women. In 1888, Osier (2) emphasized the hereditary nature of the disease, pointing out its occurrence in each of five generations, a pattern suggesting a Mendelian dominant inheritance. A positive family history, when present, is helpful in making the diagnosis. In our series of 30 patients from 24 kindreds, 7 patients had a negative family history. The parents and siblings of 6 of these 7 patients had abnormal CI esterase inhibitor (CI INH) and C4 levels. Disease in the other patient probably represents a spontaneous mutation. Twenty-seven of our patients are white, and 3 are black. Figure 2 shows a family tree depicting five generations. The propositus is in the third generation. One of the patients' siblings had scleroderma as well as hereditary angioedema. No generation is skipped, indicating a Mendelian dominant inheritance pattern.
Figure 1 . Age of onset of hereditary angioedema in 28 patients. In most cases symptoms began in childhood.
Figure 2. Pedigree of a family with hereditary angioedema, showing the typical autosomal dominant pattern of inheritance. Arrow indicates propositus.
As noted previously, the hallmarks of this disease are recurrent bouts of brawny edema of the extremities (Figure 3), face, and throat, often related to trauma, and recurrent crampy abdominal pain. The edema is usually nonpitting until the terminal phase of the attack. It is nonpruritic and nonpainful, although our patients often reported some discomfort from the "tight feeling" of skin stretched over edematous subcutaneous tissue. Trauma appeared to precipitate attacks of angioedema in 54% of our patients (Table 1). Many patients ( 4 3 % ) thought that emotional upset or anxiety provoked attacks. However, attacks can occur without trauma, as they did in several of our patients. The absence of precipitation by trauma does not exclude the diagnosis of hereditary angioedema. Although most of our patients had received thorough allergy evaluations, only five reported any allergic history at all. Patients often reported "tingling" or "tightness" at the site of the edema one half to several hours before the swelling actually occurred. However, in rare instances, this prodrome could be present 12 to 24 hours before actual edema occurred. The edema itself usually lasted for 24 to 72 hours but could range from 4 hours to 1 week. In our series, 96% of patients had attacks of angioedema involving the extremities, 85% had attacks involving the face, and 64% had an attack involving the oropharynx. Ninety-three percent of our patients reported recurrent abdominal pain as a symptom of their disease. Of these, 88% reported nausea or vomiting, or both, associated with attacks of abdominal pain. Twenty-two percent of our patients reported watery diarrhea, usually occurring late in the course of an attack. The diarrhea is caused by intraluminal fluid in the edematous gut. Extravascular fluid loss in the edematous gut causes hemoconcentration, which occasionally leads to hypotension and shock associated with these abdominal attacks. At physical examination, the abdomen was usually moderately tender but seldom rigid, owing to the lack of peritoneal involvement. Bowel sounds were usually normal or increased and occasionally highpitched. Frank et a\. • Hereditary Angioedema
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Figure 3. Typical nonpitting edema (left hand) in a patient during an attack of angioedema. The patient's normal right hand is shown for comparison.
Other investigators (4, 6, 7) have reported radiographs that show a "stacked coin" appearance with prominent spiculation and "thumbprinting," suggestive of mucosal edema (Figure 4 ) . This feature rapidly reverts to normal as the attack dissipates. One of our patients was hospitalized elsewhere with a radiographic feature identical to that of toxic megacolon. She had no previous or subsequent history of bloody diarrhea. The attack that produced this feature occurred during a cluster of abdominal attacks that were indistinguishable from the patient's usual abdominal attacks of hereditary angioedema*. Twenty-six percent of our patients said they sometimes had a nonpruritic rash with attacks of hereditary angioedema. Usually the rash preceded or accompanied the edema but sometimes occurred independently of it. Erythematous mottling, erythema multiforme, and erythema marginatum have all been described in association with attacks (2, 4, 8). Occasionally, a rash associated with angioedema may falsely suggest an immediate hypersensitivity reaction. It is important to note that none of our patients had urticaria with attacks of hereditary angioedema. On the contrary, urticaria associated with angioedema usually suggests a diagnosis other than that of hereditary angioedema. Attacks of edema involving the airway present the greatest danger to patients with this disorder ( 4 ) . Five of our 30 patients have had tracheostomies, though none have required them while actively following our treatment regimen. The attacks of pharyngeal edema were usually precipitated by dental or oropharyngeal manipulation. On occasion, airway obstruction occurred in the course of an attack that began peripherally and seemed to extend centrally, eventually involving the airway. Obstruction generally began slowly, with voice change and dysphagia heralding total obstruction. Other sites may also be involved. Two of our patients have had radiographically demonstrated transient pleural effusions with cough and mild pleuritic chest pain associated with peripheral attacks. These resolved spon* ROSEN IW: Personal communication, West Covina, California. 582
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taneously. Seizures and hemiparesis have also been reported in some patients and attributed to local cerebral edema ( 4 ) . One of the patients in our series has a history of seizures. A brain scan done after one of her seizures showed an area of cerebral hypoperfusion, possibly attributable to local edemaf. This abnormality was not seen later when the patient was asymptomatic. Menstruation and pregnancy seemed to have a major effect on disease activity. Five of 12 women reported a definite increase in attacks during their menstrual periods. The afflicted aunt of one of our patients went so far as to have a hysterectomy and oophorectomy for her disease because of this association, and she has seldom had an attack since. However, only 1 of 4 of our patients who are menopausal has reported any improvement in her disease. Two of these patients are menopausal due to hysterectomy and bilateral oophorectomy, and neither noted any decrease in the activity of her disease. Other investigators (5, 9) have also found an association of disease activity and menstruation. The effect of pregnancy is more striking. Among 10 women with a total of 25 pregnancies, none had an attack of angioedema at delivery despite the trauma to the birth canal. In 23 of 25 pregnancies, the women had markedly fewer or no attacks in the last two trimesters. Interestingly, 2 young women reported greater frequency and severity of attacks while using oral contraceptives of the combined estrogen-progesterone type. The frequency of attacks in our patients varies greatly. Some have no attacks for years and then have several attacks in a short period of time. Others may have attacks every few weeks. This shows our incomplete knowledge of time sequence of events triggering these attacks. Some unusual associations have been found with hereditary angioedema. The disease was reported in two identical twins with discoid lupus erythematosus whose mother had hereditary angioedema and systemic lupus erythematosus (10). A patient in one of our kindreds had scleroderma with hereditary angioedema. Another of our patients with t SLY W: Personal communication, St. Louis, Missouri.
Table 1. Clinical Characteristics of Hereditary Angioedema Attacks in 28 Patients
Patients %~~" Precipitating factors Trauma Anxiety or stress Signs and symptoms Peripheral angioedema Facial angioedema Pharyngeal angioedema Recurrent abdominal Pain Nausea or vomiting, or both Diarrhea Rash Most common disease manifestation Peripheral angioedema Abdominal pain
54 43 96 85 64 93 88 22 26 79 21
Figure 4 . Small bowel series taken during an abdominal attack of angioedema, showing the characteristic radiographic findings of mucosal edema with prominent "thumbprinting" and spiculation.
severe symptoms of hereditary angioedema developed bilateral facial lipodystrophy. This is significant because partial lipodystrophy has been described in patients with C3 activation, hypocomplementemia, and mesangiocapillary glomerulonephritis (11). The role, if any, of complement activation or hypocomplementemia in the production of partial lipodystrophy is unknown, but patients with hereditary angioedema have complement activation with decreased C4 and C2, and, therefore, this may be more than a chance association. Also, a syndrome clinically indistinguishable from hereditary angioedema has been reported in patients with lymphoma (12, 13). Tests in these patients showed evidence that the CI esterase inhibitor was depleted by abnormally activated CI. Pathophysiology
Dr. John P. Atkinson*: Hereditary angioedema is defined genetically and biochemically as an autosomal dominant disorder in which the function of a serum protein, the inhibitor of the first component of complement (CI INH), is markedly reduced. In this section I will discuss the genetics, structure, and function of this serum protein, the biochemical consequences of its reduced activity in hereditary angioedema patients, and our current understanding of the mechanisms of angioedema attacks. The CI esterase inhibitor has been isolated from serum as a homogeneous protein. Table 2 lists some of its characteristics (14-18). Antibodies have been raised against it, and it has been shown to be identical to a separately * Special NIH Postdoctoral Fellow in Allergy and Clinical Immunology, Washington University School of Medicine, St. Louis, Missouri. Formerly, Clinical Associate, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases.
described serum protein, alpha-2 neuraminoglycoprotein (16-18). This protein has the largest carbohydrate content of any alpha-2 glycoprotein. Fluorescent antibody to the protein binds the cut surface of hepatocytes, and therefore it is thought to be synthesized in the liver (19). It acts as an acute phase reactant, and the serum level increases in several inflammatory disorders (20). Two forms of hereditary angioedema have been described: the common and variant forms. About 85% of patients have the common form. Immunochemical and functional concentrations of the CI INH in these patients range from undetectable to about 50% of normal, with a mean level of about 15% of normal (17, 21). The remaining 15% of patients have the variant form of the disease; that is, normal or increased levels of an antigenically identical but functionally deficient protein (17). In both types, the disease is inherited as an autosomal dominant, and pedigree studies have shown that the affected patients are heterozygotes. The defect in the common form is thought to be a diminished synthesis of the inhibitor protein, and synthesis of an abnormal inhibitor produces the variant form. In both forms, Ouchterlony analysis shows antigenic identity between the CI INH of normal persons and patients with hereditary angioedema. Immunoelectrophoretic studies of the inhibitor protein from patients with the variant form, however, have shown abnormal mobility (17, 21). Thus, the common form of the disease seems to be associated with low levels of functionally and antigenically normal CI INH, whereas the variant form is associated with normal or elevated levels of a structurally and functionally altered, but antigenically intact, protein. Several theories have been advanced to account for these findings in light of the known inheritance pattern of this disease. One hypothesis attributes the common form of the disorder to a lack of one of the structural genes that codes for CI INH synthesis (22). However, this theory does not adequately account for the highly variable levels of CI INH in patients with this disease, particularly those with undetectable or very low levels. A second hypothesis attributes the disease to a disorder of gene regulation (23). The assumption here is that both structural genes are chronically repressed secondary to an abnormal repressor substance. The repressor substance may be diffusible and could reduce production of both structural genes. This possibility, based on the elegant work of Jacob and Monod with inducible enzymes in bacterial systems, is attractive because it accounts simply for how a heterzygous defect could alter production of both structural genes. Table 2. C I Inhibitor ( C I I N H ) = a - 2 Neuraminoglycoprotein
Molecular weight: 90 000 sedimentation constant 4.2S Structure: 12% hexose, 17% n-acetyl neuraminic acid Heat labile (56 °C for 60 min) Acid labile (pH < 5.5 loses all activity) Synthetic site: ? liver Plasma half-life: unknown Acute phase reactant Normal serum concentration: 15.8 ± 1.4 mg/dl (SD) Markedly reduced functional level in hereditary angioedema Frank et al. • Hereditary Angioedema
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The above analysis does not account for the variant form of hereditary angioedema. As noted earlier, kindred studies have shown that heterozygous persons are also affected in this variant. It has been suggested that the abnormality resides in the system responsible for attaching the large carbohydrate moiety to this protein (23). If so, normal antigenic concentrations of a nonfunctional protein could be present. This hypothesis is now being tested in several laboratories where abnormal and normal inhibitor are being isolated and their carbohydrate moieties compared. Functionally, CI INH is one of a series of naturally occurring inhibitors in blood of the potent effector pathways of clotting, kinin formation, fibrinolysis, and complement activation (Figure 5). It derives its name from its ability to inhibit the esterase activity of the first component of complement ( C I ) , and its function has been most thoroughly studied in the complement sequence. The first component of complement is a macromolecular protein composed of three subunits (q, r, s) (24, 25). Clq is the CI subunit that combines with antibody (26, 27). By an unknown mechanism, the formation of a Clq-antibody complex activates Clr from a proenzyme to active enzyme. C1T has protease activity and in turn activates the third CI subunit. This activated enzyme (Cls") has esterase activity that cleaves its natural substrates C4 and C2. CI INH acts in two places in the activation of CI. Primarily, it inhibits Cls", but it has also been shown to inhibit C1T. CI INH combines stoichiometrically with Cls and irreversibly blocks its action (14, 15, 27, 28). CI INH also inhibits the activity of kallikrein in the kinin system, plasma thromboplastin antecedent (factor XI of the intrinsic clotting pathway), plasmin of the fibrinolytic pathway, and, lastly, activated Hageman factor and its fragments (28, 29). In view of these multiple physiologic functions of the CI INH, one might expect several effector systems besides the complement pathway to play a role in hereditary angioedema. These facts help explain the biochemical consequences
Figure 5. Functions of the C I inhibitor. Cross bars indicate steps inhibited in the complement, clotting, kinin, and fibrinolytic pathways. PTA = plasma thromboplastin antecedent. 584
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of markedly reduced CI INH activity in patients with hereditary angioedema. The activated first component of complement (Cls) is not found in the circulation of normal persons, presumably because as soon as it is formed, it becomes complexed with and inactivated by the CI INH. Patients with hereditary and angioedema usually have low or undetectable levels of C1I between attacks, but often have free circulating CI? during attacks (30-32). C4 and C2, substrates of Cls, are chronically depressed in almost all patients (30, 33, 34). Since C4 is chronically reduced in most patients, some Cls generation probably occurs continually. Metabolic turnover studies with radiolabeled C4 have shown that the low C4 serum levels result primarily from increased use (35). A characteristic sequence of events occurs during an attack of angioedema. The level of activated Cl"s increases considerably in blood, with a concomitant decline in its substrates, C4 and C2. As the attack subsides, usually in 1 to 3 days, the levels generally return to their baseline. The C3 level remains normal throughout the attack. Protein turnover studies with 125I-labeled C3 done in six patients with hereditary angioedema showed a slight increase in the fractional catabolic rate of C3 in five of them (35, 36). One might ask why activated CI42 does not cause massive activation of C3, the next component in the sequence of reactions. The reasons are not clear, but these and other in-vivo studies suggest that the in-vivo generation of the C42 enzyme in the blood rather than on cell surfaces leads to an inefficient interaction (37, 38). The levels of histamine and kininogen were also examined during attacks. Two groups (39, 40) showed that histamine increases toward the end of an attack. This may reflect the release of C3a, a split product of C3 that acts as an anaphylatoxin and causes histamine release. There is some evidence that kallikrein substrate, kininogen, is activated and decreases during an attack (41, 42). If this were the case, then bradykinin levels should be elevated. In the only study to date, bradykinin levels were found to be slightly increased in hereditary angioedema patients, and, in two patients examined during an attack, bradykinin increased in one and decreased in the other (43). Because of the difficulty in measuring the levels of the components of the kinin system, kinin activation has not been investigated as thoroughly as complement activation and definitely needs further study. These data raise several questions: [1] How does CI or C1I become activated initially? [2] How does activated CI in turn produce edema? CI interaction with antigen-antibody complexes is the mechanism of activation most commonly studied. This may occur in infectious illnesses when antibody attaches to an invading bacterium or virus, or in immune-complex mediated diseases such as lupus erythematosus, where antigen-antibody complexes are thought to activate the complement cascade. There is no evidence that antigenantibody interactions play a role in hereditary angioedema. Although episodes of angioedema may be totally unpredictable in some persons, trauma commonly precipitated attacks in about half of our patients. Dental work is especially notorious in this regard. A reasonable sequence
of events (Figure 6) explains these clinical observations (28, 29, 44, 45). Trauma exposes endothelial and other tissue surfaces that contain negatively charged proteins (for example, collagen). These proteins, in turn, activate Hageman factor. Hageman factor activation triggers clotting, kinin generation, and fibrinolysis, the so-called Hageman factor dependent pathways. The final product of the fibrinolytic pathway is plasmin. Since plasmin activates CI from its precursor enzyme form, it may, therefore, trigger complement activation. This hypothesis is further supported by the fact that two plasmin inhibitors, epsilonaminocaproic acid and tranexamic acid, provide effective therapy in attacks of hereditary angioedema (46, 47). However, not all attacks are associated with known trauma, and some patients never have attacks associated with trauma. Thus, there may be other ways of activating the system. Once CI is activated, how does it then lead to increased capillary permeability? This point has not been settled, despite active investigation for several years (31, 32, 48, 49). The best evidence to date suggests that a small molecular weight polypeptide fragment with kinin-like activity (the so-called C2-kinin) is released during attacks of hereditary angioedema. This peptide increases capillary permeability, thereby causing angioedema. Some evidence suggests that it is derived from C2. Partially purified C l s was injected intradermally into normal persons, patients with hereditary angioedema, and patients with complement deficiencies (48-50). The C1I could produce a typical attack of angioedema in patients with hereditary angioedema but not in normal persons. These studies suggested that complement components through C2 but not beyond are necessary to increase capillary permeability. Partially purified C I , C4, and C2 produced C2-kinin in vitro, and antibody against C4 or C2, but not C3, markedly reduced its production (48, 4 9 ) . Although the evidence is suggestive, it does not rule out the participation of other serum proteins in this process, and the isolation, structure, and origin of the permeability factor remain to be definitely established. Bradykinin and histamine injected intradermally in patients do not produce angioedema and seem unlikely candidates as the mediator of the increased capillary permeability. Bradykinin injection into human skin typically produces a painful erythematous wheal, and bradykinin has a different amino acid structure from the partially purified C2-kinin fragment. Histamine produces a pruritic wheal and flare response in patients with hereditary angioedema identical to that seen in normal persons, and the response in both is partially blocked by antihistamines (48, 50, 51). Furthermore, antihistamines do not modify clinical or experimentally induced attacks of the disease (48, 50). One final, and unsolved, question of interest in the pathophysiology of hereditary angioedema is why attacks subside. It has been suggested that local tissue factors, depletion of substrates (C4 and C 2 ) , and decreased generation of C\ may be important. It should be recalled that angioedema is a localized extravascular process; there is no evidence of increased systemic capillary permeability
Figure 6. Postulated steps in the initiation of attacks of hereditary angioedema. Trauma, acting through activated Hageman factor, leads to plasmin activation and to activation of C I .
(52). However, more than local factors are involved because, in the immediate postattack period, patients are refractory to an experimentally induced episode in the opposite extremity (48). Laboratory Diagnosis
Dr. Gelfand: Laboratory confirmation of the diagnosis of hereditary angioedema depends on specific assays of proteins involved in the complement system. During attacks of angioedema, the hematocrit, leukocyte count, differential, and erythrocyte sedimentation rate are usually normal, although, as noted previously, a high leukocyte count, erythrocytosis, and hypernatremia may accompany abdominal attacks associated with sequestration of fluid and dehydration. The C3 (/SIC) assay is the complement assay used most often in clinical laboratories. This test is usually normal, although turnover studies have shown moderate hypercatabolism of C3 (35). The total hemolytic complement (CH 5 0 ) is the next most commonly used clinical assay. Although the CH 5 0 is occasionally decreased in hereditary angioedema, this test is extremely unreliable in diagnosing the disease because the CH 5 0 is often normal in hereditary angioedema and reduced in a host of other disorders ( 9 ) . As noted previously, deficient CI INH activity results in unopposed CI esterase activity, thereby causing hypercatabolism of the substrates C4 and C2. The C4 and C2 levels are thus decreased in hereditary angioedema (53). The laboratory assays that we have used to detect hereditary angioedema are similar to those used elsewhere, an assay for C4 and CI INH. Table 3 shows the various laboratory tests used to diagnose hereditary angioedema. Direct measurement of the CI INH can be done immunochemically, and antibody is commercially available. Functional assay of CI INH is done in several research laboratories (54, 55). Functional or immunochemical measurement of C4 and C2, the substrates of the CI esterase, is extremely valuable in the laboratory diagnosis of hereditary angioedema, although occasionally even these values may be normal. We screen most of our patients for both C4 and CI INH levels. When the CI INH level is normal in a patient with a low C4 level and with a clinical history consistent with hereditary angioedema, a functional assay is done Frank et al. • Hereditary Angioedema
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Table 3. Laboratory Diagnosis of Hereditary Angioedema Direct measurement of the CI inhibitor (CI INH) Immunochemical (antibodies commercially available) Functional Inhibition of EACls Inhibition of Cls esterolysis Indirect (alterations in complement proteins secondary to the absence of the CI INH) Immunochemical or functional analysis of C4 or C2 or both (C4 radial immunodiffusion plates commercially available) Reduction on CH50 titer after incubation in a low ionic strength buffer
for CI INH to identify an antigenically normal but functionally abnormal protein. Figure 7 shows the mean values of CI INH in our patients. Three patients have normal or increased levels, but their CI INH function is less than 2% of normal. Interestingly, two of these patients are two of the three black patients in our series, and they are not related to each other. About the same incidence of abnormal inhibitor is reported in other series. The level of CI INH is not affected by any known method of treatment of hereditary angioedema except plasma transfusion, which will be discussed later (46, 56). The inhibitor level correlates poorly with the activity and the severity of the disease (Figure 8). Here, the patient's disease is graded on a scale from 1 + to 4 -f on the basis of incidence and severity of attacks and resistance to treatment. Only the two most disparate groups, mild (1 + ) and severe (4 + ), are shown. Clearly, the level of CI INH does not indicate severity of disease. Drug therapy has not altered these levels (46). Figure 9 shows the range of our patients' C4 titers, several of which were within normal limits. The C4 titer falls during an attack and usually rises after an attack, though generally not to normal levels. The C4 level does not help distinguish between severely affected and mildly affected persons, but serial C4 levels in a single patient may provide some indication of disease activity. Some of our patients have had normal C4 titers with diminished CI esterase inhibitor levels, and other patients, the converse. None have ever had both measurements within the normal range. Although occasionally the C4 titer may be normal in an asymptomatic patient, we have never seen a normal C4 titer in a patient having an attack. Thus, in a patient with hereditary angioedema or unexplained recurrent abdominal pain consistent with the disease, we would determine the CI INH and C4 levels. If both are low, the common form of hereditary angioedema is the likely diagnosis. If the CI INH is low and the C4 level normal, hereditary angioedema is very likely. If the CI INH level is normal by immunochemical methods but the C4 level low, the variant form of the disease (functionally deficient CI INH) is suspected. However, other diseases that depress C4, such as systemic lupus erythematosus, could be responsible. Finally, if the CI INH and C4 levels during an attack are both normal, hereditary angioedema can be ruled out. In our experience, idiopathic nonhereditary angioedema is often associated 586
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with elevated levels of CI INH and C4, presumably acting as acute phase reactants. Differential Diagnosis
The clinical diagnosis of a patient with hereditary angioedema is not difficult when the patient complains of swelling of the face, extremities, and airway, a history of recurrent abdominal pain, and a family history of similar problems. The difficulty arises when a patient has a negative family history, a vague history of recurrent abdominal pain, or a history of unexplained swelling of the extremities or other parts of the body. The differential diagnosis must, therefore, be divided into two categories: [1] causes of recurrent abdominal pain, and [2] causes of recurrent painless swelling. The differential diagnosis of recurrent abdominal pain is beyond the scope of our paper; however, patients with hereditary angioedema generally do not show signs of peritoneal irritation, and their attacks are self-limited, usually ending within 1 to 3 days. The differential diagnosis of recurrent painless swelling is also relatively circumscribed since edema in this illness is episodic, painless, brawny, nonpitting, and not, therefore, readily confused with edema due to salt or fluid retention. The nonpruritic nature of the edema and the absence of urticaria often help to distinguish hereditary angioedema from allergic anaphylactoid edema or idiopathic angioedema. A new, recently described clinical syndrome consists of painful or pruritic urticaria-like skin lesions and angioedema in association with classic complement pathway activation and reduction of Clq, C2, C4, and C3 (57).
Figure 7. C I esterase inhibitor levels in patients with hereditary angioedema.
Proper diagnosis and availability of the necessary medical support have led to increased confidence that life-threatening attacks will be dealt with adequately. All of our patients on long-term therapy have had more than one attack per month, and all have had considerable difficulty either working or running a household because of their disease. We have chosen, as a rule, not to treat children or pregnant women because of the possibility of untoward reactions to the drugs used. Two classes of drugs are used in long-term therapy: antifibrinolytic agents and hormonal agents. The rationale for their use is not completely clear in either case. Success with antifibrinolytic agents was first described by Swedish doctors (58, 59) who reported that a patient treated with epsilonaminocaproic acid (EACA), a lysine analogue, noted relief of his disease. When these first reports became available, our group began a double-blind study of the efficacy of EACA in the treatment of hereditary angioedema (46). We thought that the study should be double blind since the severity of disease increases and decreases and is clearly influenced by emotions. Attacks occur more often in times of stress. Thus, the placebo effect may be enhanced in these patients. Figure 8. Correlation of C I esterase inhibitor levels with severity of disease. Patients with the most serious and the mildest disease are shown. There is no correlation between the inhibitor level and the severity of disease.
CI INH levels were normal in the cases reported. The patients were distinctive in that they had arthralgias, urticaria-like lesions, and some evidence of circulating immune complexes with low Clq and C3 levels. Thus, the main stumbling block to the proper diagnosis of hereditary angioedema is its omission as a diagnostic consideration. In our 30 patients, the mean duration from the onset of symptoms to the actual diagnosis of hereditary angioedema was 21 years. The diagnoses entertained in the interim included psychosomatic illness, small bowel obstruction, acute appendicitis, ulcer disease, and even acute rheumatic fever. Five of our patients had undergone exploratory laparotomy for abdominal pain, and in several others normal appendixes or ovaries were removed.
The criteria for attacks, as well as those for diagnosis of the disease, were carefully defined before the closed sequential trial was begun. Patients received EACA or placebo for 1 month or until they had an attack of angioedema. When the patient received a course for 1 month or had an attack, the next course was begun. Courses of drug and placebo were chosen by random allocation, and, therefore, a patient could
Therapy
Dr. Frank: Clinicians must consider three phases of therapy in treating patients with hereditary angioedema (Table 4 ) : [1] long-term prophylaxis of attacks; [2] shortterm prophylaxis of attacks; and [3] treatment of acute attacks. LONG-TERM THERAPY
Long-term therapy is not required for all patients with hereditary angioedema. Attacks in most patients are probably sufficiently mild or infrequent so that they do not require long-term treatment. Despite the theoretical possibility of a life-threatening episode, we have not initiated long-term therapy unless the patient has already had partial laryngeal obstruction, repeated episodes of swelling about the face and neck, or frequent debilitating attacks.
Hereditary Angioedema: the Clinical Syndrome and Its Management Moderator:
MICHAEL M. FRANK, M.D.;
Discussants: JEFFREY A. GELFAND, M.D.; and
JOHN P. ATKINSON, M.D.; Bethesda, Maryland
Hereditary angioedema is manifested by attacks of swelling of the extremities, face, trunk, airway, or abdominal viscera, occurring spontaneously or secondary to trauma. It is inherited as an autosomal dominant trait and is due to deficient activity of the inhibitor of the activated first component of complement. The clinical diagnosis can be confirmed by the findings of low levels of C4 or C I esterase inhibitor activity, or both. Therapy may be divided into three phases: long-term prophylaxis of attacks, short-term prophylaxis of attacks, and treatment of acute attacks. Long-term prophylaxis may be achieved with antifibrinolytic agents and androgens. Short-term prophylaxis with these agents and plasma transfusions has been successful. Specific therapy for acute attacks is not available, but good supportive care, together with a knowledge of the course of the disease, can prevent asphyxiation from airway obstruction. Before the advent of therapy, mortality was reported as high as 3 0 % .
DR. MICHAEL M. FRANK*: Recently, hereditary angioedema has received increasing attention in the medical literature because it is an important example of the socalled "experiments of nature," which include diseases that are characterized by a well-defined, circumscribed biochemical or cellular defect that provides an opportunity to define basic pathophysiologic mechanisms. Although the clinical entity has been defined for many years (1, 2), the biochemical abnormality responsible for the development of the illness has been identified only recently (3). With our greater knowledge of the pathophysiology of this disease, we realize that study of it may provide a better understanding of the normal function of several of the enzyme systems in plasma. We think of hereditary angioedema as a disease that affects not only the complement system, but also the * Head, Clinical Immunology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases. • An edited transcription of a Combined Clinical Staff Conference at the Clinical Center, Bethesda, Maryland, 9 January 1975, by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S. Department of Health, Education, and Welfare. 580
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kinin-generating and fibrinolytic systems. Most of the recent reports on hereditary angioedema have dealt with its pathophysiology. The clinical literature has pointed out the high mortality associated with the disease and the difficulty in treating attacks (4, 5). However, relatively little attention has been paid to the clinical syndrome and therapy of this condition. Thus, a clinician caring for a patient with this potentially life-threatening illness does not have one source to consult for current developments in therapy. Patients with hereditary angioedema have been treated at the Clinical Center for the past 6 years. We review here our current understanding of the disease, with special attention to the clinical manifestations that we have seen in our patients and management of the various clinical problems that may develop. The Clinical Syndrome
Dr. Jeffrey A. Gelfandf: Hereditary angioedema has a significant morbidity rate, which rises markedly when the disease is unsuspected and undiagnosed. Our patients had symptoms for an average of 21 years before hereditary angioedema was diagnosed. We report here the clinical characteristics of 30 patients with hereditary angioedema who were followed closely at the Clinical Center. For estimates of mortality, we questioned our patients about their family members. Including family members whose serum we were able to test and those with a clear clinical history, we studied a total of 72 affected persons. Of these, 10 died from the disease or its complications. Although our referral population may represent a biased sample, these figures nevertheless indicate how severe the disease may be and how late in its course it may be diagnosed. The cardinal symptoms of hereditary angioedema are edema of the extremities, face, and airway, and recurrent abdominal pain (1, 2, 4, 5); they are not mutually exclusive and may be seen in combination. We questioned our patients about the onset of their illness. Seventy-five percent remembered swelling of the extremities as a t Clinical Associate, Clinical Immunology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases.
presenting sign, 36% recalled swelling of the face or throat, and 52% recalled recurrent bouts of abdominal pain. In our series, 39% of the patients could attribute their first episode to a clearly identifiable traumatic event such as tonsillectomy, dental manipulation, or accidental trauma. This is probably a conservative estimate of the incidence of trauma in the initial presentation of the disease, as patients later learned to regard some relatively simple activities as having traumatic potential. Patients have mentioned that activities such as typing, prolonged writing, pushing a lawn mower, hammering, or even standing in place for several hours will provoke edema in the extremities involved. Activities such as sexual intercourse and horseback riding have produced edema of the genitalia in some of our patients. Age was of minimal help in making the diagnosis. Our patients range in age from 10 to 72 years. More than half of them noted the onset of their symptoms before the age of 7, and over two thirds became symptomatic before age 13 (Figure 1). This is in contrast to idiopathic angioedema in which onset generally occurs in adult life. However, our oldest patient, now 72 years old, became symptomatic after age 50. The age of onset was not significantly different between men and women. In 1888, Osier (2) emphasized the hereditary nature of the disease, pointing out its occurrence in each of five generations, a pattern suggesting a Mendelian dominant inheritance. A positive family history, when present, is helpful in making the diagnosis. In our series of 30 patients from 24 kindreds, 7 patients had a negative family history. The parents and siblings of 6 of these 7 patients had abnormal CI esterase inhibitor (CI INH) and C4 levels. Disease in the other patient probably represents a spontaneous mutation. Twenty-seven of our patients are white, and 3 are black. Figure 2 shows a family tree depicting five generations. The propositus is in the third generation. One of the patients' siblings had scleroderma as well as hereditary angioedema. No generation is skipped, indicating a Mendelian dominant inheritance pattern.
Figure 1 . Age of onset of hereditary angioedema in 28 patients. In most cases symptoms began in childhood.
Figure 2. Pedigree of a family with hereditary angioedema, showing the typical autosomal dominant pattern of inheritance. Arrow indicates propositus.
As noted previously, the hallmarks of this disease are recurrent bouts of brawny edema of the extremities (Figure 3), face, and throat, often related to trauma, and recurrent crampy abdominal pain. The edema is usually nonpitting until the terminal phase of the attack. It is nonpruritic and nonpainful, although our patients often reported some discomfort from the "tight feeling" of skin stretched over edematous subcutaneous tissue. Trauma appeared to precipitate attacks of angioedema in 54% of our patients (Table 1). Many patients ( 4 3 % ) thought that emotional upset or anxiety provoked attacks. However, attacks can occur without trauma, as they did in several of our patients. The absence of precipitation by trauma does not exclude the diagnosis of hereditary angioedema. Although most of our patients had received thorough allergy evaluations, only five reported any allergic history at all. Patients often reported "tingling" or "tightness" at the site of the edema one half to several hours before the swelling actually occurred. However, in rare instances, this prodrome could be present 12 to 24 hours before actual edema occurred. The edema itself usually lasted for 24 to 72 hours but could range from 4 hours to 1 week. In our series, 96% of patients had attacks of angioedema involving the extremities, 85% had attacks involving the face, and 64% had an attack involving the oropharynx. Ninety-three percent of our patients reported recurrent abdominal pain as a symptom of their disease. Of these, 88% reported nausea or vomiting, or both, associated with attacks of abdominal pain. Twenty-two percent of our patients reported watery diarrhea, usually occurring late in the course of an attack. The diarrhea is caused by intraluminal fluid in the edematous gut. Extravascular fluid loss in the edematous gut causes hemoconcentration, which occasionally leads to hypotension and shock associated with these abdominal attacks. At physical examination, the abdomen was usually moderately tender but seldom rigid, owing to the lack of peritoneal involvement. Bowel sounds were usually normal or increased and occasionally highpitched. Frank et a\. • Hereditary Angioedema
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Figure 3. Typical nonpitting edema (left hand) in a patient during an attack of angioedema. The patient's normal right hand is shown for comparison.
Other investigators (4, 6, 7) have reported radiographs that show a "stacked coin" appearance with prominent spiculation and "thumbprinting," suggestive of mucosal edema (Figure 4 ) . This feature rapidly reverts to normal as the attack dissipates. One of our patients was hospitalized elsewhere with a radiographic feature identical to that of toxic megacolon. She had no previous or subsequent history of bloody diarrhea. The attack that produced this feature occurred during a cluster of abdominal attacks that were indistinguishable from the patient's usual abdominal attacks of hereditary angioedema*. Twenty-six percent of our patients said they sometimes had a nonpruritic rash with attacks of hereditary angioedema. Usually the rash preceded or accompanied the edema but sometimes occurred independently of it. Erythematous mottling, erythema multiforme, and erythema marginatum have all been described in association with attacks (2, 4, 8). Occasionally, a rash associated with angioedema may falsely suggest an immediate hypersensitivity reaction. It is important to note that none of our patients had urticaria with attacks of hereditary angioedema. On the contrary, urticaria associated with angioedema usually suggests a diagnosis other than that of hereditary angioedema. Attacks of edema involving the airway present the greatest danger to patients with this disorder ( 4 ) . Five of our 30 patients have had tracheostomies, though none have required them while actively following our treatment regimen. The attacks of pharyngeal edema were usually precipitated by dental or oropharyngeal manipulation. On occasion, airway obstruction occurred in the course of an attack that began peripherally and seemed to extend centrally, eventually involving the airway. Obstruction generally began slowly, with voice change and dysphagia heralding total obstruction. Other sites may also be involved. Two of our patients have had radiographically demonstrated transient pleural effusions with cough and mild pleuritic chest pain associated with peripheral attacks. These resolved spon* ROSEN IW: Personal communication, West Covina, California. 582
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taneously. Seizures and hemiparesis have also been reported in some patients and attributed to local cerebral edema ( 4 ) . One of the patients in our series has a history of seizures. A brain scan done after one of her seizures showed an area of cerebral hypoperfusion, possibly attributable to local edemaf. This abnormality was not seen later when the patient was asymptomatic. Menstruation and pregnancy seemed to have a major effect on disease activity. Five of 12 women reported a definite increase in attacks during their menstrual periods. The afflicted aunt of one of our patients went so far as to have a hysterectomy and oophorectomy for her disease because of this association, and she has seldom had an attack since. However, only 1 of 4 of our patients who are menopausal has reported any improvement in her disease. Two of these patients are menopausal due to hysterectomy and bilateral oophorectomy, and neither noted any decrease in the activity of her disease. Other investigators (5, 9) have also found an association of disease activity and menstruation. The effect of pregnancy is more striking. Among 10 women with a total of 25 pregnancies, none had an attack of angioedema at delivery despite the trauma to the birth canal. In 23 of 25 pregnancies, the women had markedly fewer or no attacks in the last two trimesters. Interestingly, 2 young women reported greater frequency and severity of attacks while using oral contraceptives of the combined estrogen-progesterone type. The frequency of attacks in our patients varies greatly. Some have no attacks for years and then have several attacks in a short period of time. Others may have attacks every few weeks. This shows our incomplete knowledge of time sequence of events triggering these attacks. Some unusual associations have been found with hereditary angioedema. The disease was reported in two identical twins with discoid lupus erythematosus whose mother had hereditary angioedema and systemic lupus erythematosus (10). A patient in one of our kindreds had scleroderma with hereditary angioedema. Another of our patients with t SLY W: Personal communication, St. Louis, Missouri.
Table 1. Clinical Characteristics of Hereditary Angioedema Attacks in 28 Patients
Patients %~~" Precipitating factors Trauma Anxiety or stress Signs and symptoms Peripheral angioedema Facial angioedema Pharyngeal angioedema Recurrent abdominal Pain Nausea or vomiting, or both Diarrhea Rash Most common disease manifestation Peripheral angioedema Abdominal pain
54 43 96 85 64 93 88 22 26 79 21
Figure 4 . Small bowel series taken during an abdominal attack of angioedema, showing the characteristic radiographic findings of mucosal edema with prominent "thumbprinting" and spiculation.
severe symptoms of hereditary angioedema developed bilateral facial lipodystrophy. This is significant because partial lipodystrophy has been described in patients with C3 activation, hypocomplementemia, and mesangiocapillary glomerulonephritis (11). The role, if any, of complement activation or hypocomplementemia in the production of partial lipodystrophy is unknown, but patients with hereditary angioedema have complement activation with decreased C4 and C2, and, therefore, this may be more than a chance association. Also, a syndrome clinically indistinguishable from hereditary angioedema has been reported in patients with lymphoma (12, 13). Tests in these patients showed evidence that the CI esterase inhibitor was depleted by abnormally activated CI. Pathophysiology
Dr. John P. Atkinson*: Hereditary angioedema is defined genetically and biochemically as an autosomal dominant disorder in which the function of a serum protein, the inhibitor of the first component of complement (CI INH), is markedly reduced. In this section I will discuss the genetics, structure, and function of this serum protein, the biochemical consequences of its reduced activity in hereditary angioedema patients, and our current understanding of the mechanisms of angioedema attacks. The CI esterase inhibitor has been isolated from serum as a homogeneous protein. Table 2 lists some of its characteristics (14-18). Antibodies have been raised against it, and it has been shown to be identical to a separately * Special NIH Postdoctoral Fellow in Allergy and Clinical Immunology, Washington University School of Medicine, St. Louis, Missouri. Formerly, Clinical Associate, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases.
described serum protein, alpha-2 neuraminoglycoprotein (16-18). This protein has the largest carbohydrate content of any alpha-2 glycoprotein. Fluorescent antibody to the protein binds the cut surface of hepatocytes, and therefore it is thought to be synthesized in the liver (19). It acts as an acute phase reactant, and the serum level increases in several inflammatory disorders (20). Two forms of hereditary angioedema have been described: the common and variant forms. About 85% of patients have the common form. Immunochemical and functional concentrations of the CI INH in these patients range from undetectable to about 50% of normal, with a mean level of about 15% of normal (17, 21). The remaining 15% of patients have the variant form of the disease; that is, normal or increased levels of an antigenically identical but functionally deficient protein (17). In both types, the disease is inherited as an autosomal dominant, and pedigree studies have shown that the affected patients are heterozygotes. The defect in the common form is thought to be a diminished synthesis of the inhibitor protein, and synthesis of an abnormal inhibitor produces the variant form. In both forms, Ouchterlony analysis shows antigenic identity between the CI INH of normal persons and patients with hereditary angioedema. Immunoelectrophoretic studies of the inhibitor protein from patients with the variant form, however, have shown abnormal mobility (17, 21). Thus, the common form of the disease seems to be associated with low levels of functionally and antigenically normal CI INH, whereas the variant form is associated with normal or elevated levels of a structurally and functionally altered, but antigenically intact, protein. Several theories have been advanced to account for these findings in light of the known inheritance pattern of this disease. One hypothesis attributes the common form of the disorder to a lack of one of the structural genes that codes for CI INH synthesis (22). However, this theory does not adequately account for the highly variable levels of CI INH in patients with this disease, particularly those with undetectable or very low levels. A second hypothesis attributes the disease to a disorder of gene regulation (23). The assumption here is that both structural genes are chronically repressed secondary to an abnormal repressor substance. The repressor substance may be diffusible and could reduce production of both structural genes. This possibility, based on the elegant work of Jacob and Monod with inducible enzymes in bacterial systems, is attractive because it accounts simply for how a heterzygous defect could alter production of both structural genes. Table 2. C I Inhibitor ( C I I N H ) = a - 2 Neuraminoglycoprotein
Molecular weight: 90 000 sedimentation constant 4.2S Structure: 12% hexose, 17% n-acetyl neuraminic acid Heat labile (56 °C for 60 min) Acid labile (pH < 5.5 loses all activity) Synthetic site: ? liver Plasma half-life: unknown Acute phase reactant Normal serum concentration: 15.8 ± 1.4 mg/dl (SD) Markedly reduced functional level in hereditary angioedema Frank et al. • Hereditary Angioedema
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The above analysis does not account for the variant form of hereditary angioedema. As noted earlier, kindred studies have shown that heterozygous persons are also affected in this variant. It has been suggested that the abnormality resides in the system responsible for attaching the large carbohydrate moiety to this protein (23). If so, normal antigenic concentrations of a nonfunctional protein could be present. This hypothesis is now being tested in several laboratories where abnormal and normal inhibitor are being isolated and their carbohydrate moieties compared. Functionally, CI INH is one of a series of naturally occurring inhibitors in blood of the potent effector pathways of clotting, kinin formation, fibrinolysis, and complement activation (Figure 5). It derives its name from its ability to inhibit the esterase activity of the first component of complement ( C I ) , and its function has been most thoroughly studied in the complement sequence. The first component of complement is a macromolecular protein composed of three subunits (q, r, s) (24, 25). Clq is the CI subunit that combines with antibody (26, 27). By an unknown mechanism, the formation of a Clq-antibody complex activates Clr from a proenzyme to active enzyme. C1T has protease activity and in turn activates the third CI subunit. This activated enzyme (Cls") has esterase activity that cleaves its natural substrates C4 and C2. CI INH acts in two places in the activation of CI. Primarily, it inhibits Cls", but it has also been shown to inhibit C1T. CI INH combines stoichiometrically with Cls and irreversibly blocks its action (14, 15, 27, 28). CI INH also inhibits the activity of kallikrein in the kinin system, plasma thromboplastin antecedent (factor XI of the intrinsic clotting pathway), plasmin of the fibrinolytic pathway, and, lastly, activated Hageman factor and its fragments (28, 29). In view of these multiple physiologic functions of the CI INH, one might expect several effector systems besides the complement pathway to play a role in hereditary angioedema. These facts help explain the biochemical consequences
Figure 5. Functions of the C I inhibitor. Cross bars indicate steps inhibited in the complement, clotting, kinin, and fibrinolytic pathways. PTA = plasma thromboplastin antecedent. 584
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of markedly reduced CI INH activity in patients with hereditary angioedema. The activated first component of complement (Cls) is not found in the circulation of normal persons, presumably because as soon as it is formed, it becomes complexed with and inactivated by the CI INH. Patients with hereditary and angioedema usually have low or undetectable levels of C1I between attacks, but often have free circulating CI? during attacks (30-32). C4 and C2, substrates of Cls, are chronically depressed in almost all patients (30, 33, 34). Since C4 is chronically reduced in most patients, some Cls generation probably occurs continually. Metabolic turnover studies with radiolabeled C4 have shown that the low C4 serum levels result primarily from increased use (35). A characteristic sequence of events occurs during an attack of angioedema. The level of activated Cl"s increases considerably in blood, with a concomitant decline in its substrates, C4 and C2. As the attack subsides, usually in 1 to 3 days, the levels generally return to their baseline. The C3 level remains normal throughout the attack. Protein turnover studies with 125I-labeled C3 done in six patients with hereditary angioedema showed a slight increase in the fractional catabolic rate of C3 in five of them (35, 36). One might ask why activated CI42 does not cause massive activation of C3, the next component in the sequence of reactions. The reasons are not clear, but these and other in-vivo studies suggest that the in-vivo generation of the C42 enzyme in the blood rather than on cell surfaces leads to an inefficient interaction (37, 38). The levels of histamine and kininogen were also examined during attacks. Two groups (39, 40) showed that histamine increases toward the end of an attack. This may reflect the release of C3a, a split product of C3 that acts as an anaphylatoxin and causes histamine release. There is some evidence that kallikrein substrate, kininogen, is activated and decreases during an attack (41, 42). If this were the case, then bradykinin levels should be elevated. In the only study to date, bradykinin levels were found to be slightly increased in hereditary angioedema patients, and, in two patients examined during an attack, bradykinin increased in one and decreased in the other (43). Because of the difficulty in measuring the levels of the components of the kinin system, kinin activation has not been investigated as thoroughly as complement activation and definitely needs further study. These data raise several questions: [1] How does CI or C1I become activated initially? [2] How does activated CI in turn produce edema? CI interaction with antigen-antibody complexes is the mechanism of activation most commonly studied. This may occur in infectious illnesses when antibody attaches to an invading bacterium or virus, or in immune-complex mediated diseases such as lupus erythematosus, where antigen-antibody complexes are thought to activate the complement cascade. There is no evidence that antigenantibody interactions play a role in hereditary angioedema. Although episodes of angioedema may be totally unpredictable in some persons, trauma commonly precipitated attacks in about half of our patients. Dental work is especially notorious in this regard. A reasonable sequence
of events (Figure 6) explains these clinical observations (28, 29, 44, 45). Trauma exposes endothelial and other tissue surfaces that contain negatively charged proteins (for example, collagen). These proteins, in turn, activate Hageman factor. Hageman factor activation triggers clotting, kinin generation, and fibrinolysis, the so-called Hageman factor dependent pathways. The final product of the fibrinolytic pathway is plasmin. Since plasmin activates CI from its precursor enzyme form, it may, therefore, trigger complement activation. This hypothesis is further supported by the fact that two plasmin inhibitors, epsilonaminocaproic acid and tranexamic acid, provide effective therapy in attacks of hereditary angioedema (46, 47). However, not all attacks are associated with known trauma, and some patients never have attacks associated with trauma. Thus, there may be other ways of activating the system. Once CI is activated, how does it then lead to increased capillary permeability? This point has not been settled, despite active investigation for several years (31, 32, 48, 49). The best evidence to date suggests that a small molecular weight polypeptide fragment with kinin-like activity (the so-called C2-kinin) is released during attacks of hereditary angioedema. This peptide increases capillary permeability, thereby causing angioedema. Some evidence suggests that it is derived from C2. Partially purified C l s was injected intradermally into normal persons, patients with hereditary angioedema, and patients with complement deficiencies (48-50). The C1I could produce a typical attack of angioedema in patients with hereditary angioedema but not in normal persons. These studies suggested that complement components through C2 but not beyond are necessary to increase capillary permeability. Partially purified C I , C4, and C2 produced C2-kinin in vitro, and antibody against C4 or C2, but not C3, markedly reduced its production (48, 4 9 ) . Although the evidence is suggestive, it does not rule out the participation of other serum proteins in this process, and the isolation, structure, and origin of the permeability factor remain to be definitely established. Bradykinin and histamine injected intradermally in patients do not produce angioedema and seem unlikely candidates as the mediator of the increased capillary permeability. Bradykinin injection into human skin typically produces a painful erythematous wheal, and bradykinin has a different amino acid structure from the partially purified C2-kinin fragment. Histamine produces a pruritic wheal and flare response in patients with hereditary angioedema identical to that seen in normal persons, and the response in both is partially blocked by antihistamines (48, 50, 51). Furthermore, antihistamines do not modify clinical or experimentally induced attacks of the disease (48, 50). One final, and unsolved, question of interest in the pathophysiology of hereditary angioedema is why attacks subside. It has been suggested that local tissue factors, depletion of substrates (C4 and C 2 ) , and decreased generation of C\ may be important. It should be recalled that angioedema is a localized extravascular process; there is no evidence of increased systemic capillary permeability
Figure 6. Postulated steps in the initiation of attacks of hereditary angioedema. Trauma, acting through activated Hageman factor, leads to plasmin activation and to activation of C I .
(52). However, more than local factors are involved because, in the immediate postattack period, patients are refractory to an experimentally induced episode in the opposite extremity (48). Laboratory Diagnosis
Dr. Gelfand: Laboratory confirmation of the diagnosis of hereditary angioedema depends on specific assays of proteins involved in the complement system. During attacks of angioedema, the hematocrit, leukocyte count, differential, and erythrocyte sedimentation rate are usually normal, although, as noted previously, a high leukocyte count, erythrocytosis, and hypernatremia may accompany abdominal attacks associated with sequestration of fluid and dehydration. The C3 (/SIC) assay is the complement assay used most often in clinical laboratories. This test is usually normal, although turnover studies have shown moderate hypercatabolism of C3 (35). The total hemolytic complement (CH 5 0 ) is the next most commonly used clinical assay. Although the CH 5 0 is occasionally decreased in hereditary angioedema, this test is extremely unreliable in diagnosing the disease because the CH 5 0 is often normal in hereditary angioedema and reduced in a host of other disorders ( 9 ) . As noted previously, deficient CI INH activity results in unopposed CI esterase activity, thereby causing hypercatabolism of the substrates C4 and C2. The C4 and C2 levels are thus decreased in hereditary angioedema (53). The laboratory assays that we have used to detect hereditary angioedema are similar to those used elsewhere, an assay for C4 and CI INH. Table 3 shows the various laboratory tests used to diagnose hereditary angioedema. Direct measurement of the CI INH can be done immunochemically, and antibody is commercially available. Functional assay of CI INH is done in several research laboratories (54, 55). Functional or immunochemical measurement of C4 and C2, the substrates of the CI esterase, is extremely valuable in the laboratory diagnosis of hereditary angioedema, although occasionally even these values may be normal. We screen most of our patients for both C4 and CI INH levels. When the CI INH level is normal in a patient with a low C4 level and with a clinical history consistent with hereditary angioedema, a functional assay is done Frank et al. • Hereditary Angioedema
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Table 3. Laboratory Diagnosis of Hereditary Angioedema Direct measurement of the CI inhibitor (CI INH) Immunochemical (antibodies commercially available) Functional Inhibition of EACls Inhibition of Cls esterolysis Indirect (alterations in complement proteins secondary to the absence of the CI INH) Immunochemical or functional analysis of C4 or C2 or both (C4 radial immunodiffusion plates commercially available) Reduction on CH50 titer after incubation in a low ionic strength buffer
for CI INH to identify an antigenically normal but functionally abnormal protein. Figure 7 shows the mean values of CI INH in our patients. Three patients have normal or increased levels, but their CI INH function is less than 2% of normal. Interestingly, two of these patients are two of the three black patients in our series, and they are not related to each other. About the same incidence of abnormal inhibitor is reported in other series. The level of CI INH is not affected by any known method of treatment of hereditary angioedema except plasma transfusion, which will be discussed later (46, 56). The inhibitor level correlates poorly with the activity and the severity of the disease (Figure 8). Here, the patient's disease is graded on a scale from 1 + to 4 -f on the basis of incidence and severity of attacks and resistance to treatment. Only the two most disparate groups, mild (1 + ) and severe (4 + ), are shown. Clearly, the level of CI INH does not indicate severity of disease. Drug therapy has not altered these levels (46). Figure 9 shows the range of our patients' C4 titers, several of which were within normal limits. The C4 titer falls during an attack and usually rises after an attack, though generally not to normal levels. The C4 level does not help distinguish between severely affected and mildly affected persons, but serial C4 levels in a single patient may provide some indication of disease activity. Some of our patients have had normal C4 titers with diminished CI esterase inhibitor levels, and other patients, the converse. None have ever had both measurements within the normal range. Although occasionally the C4 titer may be normal in an asymptomatic patient, we have never seen a normal C4 titer in a patient having an attack. Thus, in a patient with hereditary angioedema or unexplained recurrent abdominal pain consistent with the disease, we would determine the CI INH and C4 levels. If both are low, the common form of hereditary angioedema is the likely diagnosis. If the CI INH is low and the C4 level normal, hereditary angioedema is very likely. If the CI INH level is normal by immunochemical methods but the C4 level low, the variant form of the disease (functionally deficient CI INH) is suspected. However, other diseases that depress C4, such as systemic lupus erythematosus, could be responsible. Finally, if the CI INH and C4 levels during an attack are both normal, hereditary angioedema can be ruled out. In our experience, idiopathic nonhereditary angioedema is often associated 586
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with elevated levels of CI INH and C4, presumably acting as acute phase reactants. Differential Diagnosis
The clinical diagnosis of a patient with hereditary angioedema is not difficult when the patient complains of swelling of the face, extremities, and airway, a history of recurrent abdominal pain, and a family history of similar problems. The difficulty arises when a patient has a negative family history, a vague history of recurrent abdominal pain, or a history of unexplained swelling of the extremities or other parts of the body. The differential diagnosis must, therefore, be divided into two categories: [1] causes of recurrent abdominal pain, and [2] causes of recurrent painless swelling. The differential diagnosis of recurrent abdominal pain is beyond the scope of our paper; however, patients with hereditary angioedema generally do not show signs of peritoneal irritation, and their attacks are self-limited, usually ending within 1 to 3 days. The differential diagnosis of recurrent painless swelling is also relatively circumscribed since edema in this illness is episodic, painless, brawny, nonpitting, and not, therefore, readily confused with edema due to salt or fluid retention. The nonpruritic nature of the edema and the absence of urticaria often help to distinguish hereditary angioedema from allergic anaphylactoid edema or idiopathic angioedema. A new, recently described clinical syndrome consists of painful or pruritic urticaria-like skin lesions and angioedema in association with classic complement pathway activation and reduction of Clq, C2, C4, and C3 (57).
Figure 7. C I esterase inhibitor levels in patients with hereditary angioedema.
Proper diagnosis and availability of the necessary medical support have led to increased confidence that life-threatening attacks will be dealt with adequately. All of our patients on long-term therapy have had more than one attack per month, and all have had considerable difficulty either working or running a household because of their disease. We have chosen, as a rule, not to treat children or pregnant women because of the possibility of untoward reactions to the drugs used. Two classes of drugs are used in long-term therapy: antifibrinolytic agents and hormonal agents. The rationale for their use is not completely clear in either case. Success with antifibrinolytic agents was first described by Swedish doctors (58, 59) who reported that a patient treated with epsilonaminocaproic acid (EACA), a lysine analogue, noted relief of his disease. When these first reports became available, our group began a double-blind study of the efficacy of EACA in the treatment of hereditary angioedema (46). We thought that the study should be double blind since the severity of disease increases and decreases and is clearly influenced by emotions. Attacks occur more often in times of stress. Thus, the placebo effect may be enhanced in these patients. Figure 8. Correlation of C I esterase inhibitor levels with severity of disease. Patients with the most serious and the mildest disease are shown. There is no correlation between the inhibitor level and the severity of disease.
CI INH levels were normal in the cases reported. The patients were distinctive in that they had arthralgias, urticaria-like lesions, and some evidence of circulating immune complexes with low Clq and C3 levels. Thus, the main stumbling block to the proper diagnosis of hereditary angioedema is its omission as a diagnostic consideration. In our 30 patients, the mean duration from the onset of symptoms to the actual diagnosis of hereditary angioedema was 21 years. The diagnoses entertained in the interim included psychosomatic illness, small bowel obstruction, acute appendicitis, ulcer disease, and even acute rheumatic fever. Five of our patients had undergone exploratory laparotomy for abdominal pain, and in several others normal appendixes or ovaries were removed.
The criteria for attacks, as well as those for diagnosis of the disease, were carefully defined before the closed sequential trial was begun. Patients received EACA or placebo for 1 month or until they had an attack of angioedema. When the patient received a course for 1 month or had an attack, the next course was begun. Courses of drug and placebo were chosen by random allocation, and, therefore, a patient could
Therapy
Dr. Frank: Clinicians must consider three phases of therapy in treating patients with hereditary angioedema (Table 4 ) : [1] long-term prophylaxis of attacks; [2] shortterm prophylaxis of attacks; and [3] treatment of acute attacks. LONG-TERM THERAPY
Long-term therapy is not required for all patients with hereditary angioedema. Attacks in most patients are probably sufficiently mild or infrequent so that they do not require long-term treatment. Despite the theoretical possibility of a life-threatening episode, we have not initiated long-term therapy unless the patient has already had partial laryngeal obstruction, repeated episodes of swelling about the face and neck, or frequent debilitating attacks.
