Hereditary Angioedema: a Broad Review for Clinicians

REVIEW ARTICLE Hereditary Angioedema A Broad Review for Clinicians

Ugochukwu C. Nzeako, MD, MPH; Evangelo Frigas, MD; William J. Tremaine, MD

ereditary angioedema (HAE) is an autosomal dominant disease that afflicts 1 in 10000 to 1 in 150000 persons; HAE has been reported in all races, and no sex predominance has been found. It manifests as recurrent attacks of intense, massive, localized edema without concomitant pruritus, often resulting from one of several known trig- Hgers. However, attacks can occur in the absence of any identifiable initiating event. Historically, 2 types of HAE have been described. However, a variant, possibly X-linked, inherited angioedema has recently been described, and tentatively it has been named “type 3” HAE. Signs and symptoms are identical in all types of HAE. Skin and visceral organs may be involved by the typically massive local edema. The most commonly involved viscera are the respiratory and gastrointestinal systems. Involvement of the upper airways can result in severe life-threatening symptoms, including the risk of asphyxiation, unless appropriate interventions are taken. Quantitative and functional analyses of C1 esterase inhibitor and complement components C4 and C1q should be performed when HAE is suspected. Acute exacerbations of the disease should be treated with intravenous purified C1 esterase inhibitor concentrate, where available. Intravenous administration of fresh frozen plasma is also useful in acute HAE; however, it occasionally exacerbates symptoms. Corti- costeroids, antihistamines, and epinephrine can be useful adjuncts but typically are not efficacious in aborting acute attacks. Prophylactic management involves long-term use of attenuated androgens or antifibrinolytic agents. Clinicians should keep this disorder in their differential diagnosis of unexplained, episodic cutaneous angioedema or abdominal pain. Arch Intern Med. 2001;161:2417-2429

Angioedema is an intense, usually disfig- prescribed for common ailments, such as uring, temporary swelling of a localized angiotensin-converting enzyme (ACE) body area. It most commonly occurs as inhibitors for hypertension, renal dis- part of an allergic response to exogenous ease, and cardiac disease, can also induce substances and conditions. Such sub- an adverse reaction in apparently healthy stances may be dietary in origin, eg, shell- individuals and result in angioedema. fish and other seafood, or may be environmental, as is the case with tempera- See also page 2406 ture-related angioedema. The sporadic exogenous phenomena that result in an- In a few individuals, angioedema oc- gioedema may be prevalent in up to 10% curs because of an intrinsic defect that abol- of the population.1 Use of some drugs ishes one of the body’s several safeguards against such occurrences. This defect al- From the Divisions of Gastroenterology (Drs Nzeako and Tremaine), Hepatology lows a cascade of events that culminates in (Drs Nzeako and Tremaine), and Allergy (Dr Frigas), Mayo Clinic and Foundation, symptoms. This form of angioedema oc- Rochester, Minn. curs as a result of either an inherited defect

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 in C1 esterase inhibitor (C1-INH) ac- pathophysiology, and genetic basis of in individuals as young as 4 weeks and tivity or an acquired deficiency of C1- the various forms of angioedema has as old as 78 years. Patients with no INH. The inherited form of the broadened considerably. previous history of upper airway in- disease, known as hereditary angio- volvement during acute HAE exac- edema (HAE), is rare, although it is CLINICAL PRESENTATION erbations still run a risk of asphyxi- more common than acquired angio- ating. In a recent study,11 5of6 edema (AAE). Symptoms of HAE are usually mild individuals who asphyxiated during Traditionally, 2 types of HAE or nonexistent during early child- acute HAE had never experienced up- have been described. Type 1 HAE, hood, typically first manifesting dur- per airway involvement during pre- which is estimated to occur in 80% to ing the second decade of life. How- vious attacks. The time from symp- 85% of patients, is caused by the de- ever, a few patients present during tom onset to asphyxiation also varies, creased production of C1-INH, result- their first decade. Although some at- ranging from as little as 20 minutes ing in subnormal blood and tissue in- tacks lack an identifiable trigger, most to as long as 14 hours. Transient pleu- hibitor activity. In type 2 HAE, which are associated with trauma, medical ral effusions, sometimes with cough occurs in the remaining 15% to 20% procedures, emotional stress, men- and mild pleuritic chest pain, can also of patients, normal or elevated quan- struation, oral contraceptive use, in- occur.9 titiesoffunctionallyimpairedC1-INH fections, or the use of medications Gastrointestinal tract symp- are produced. Recently, a third type such as ACE inhibitors.7 toms of HAE, caused by visceral of HAE in which C1-INH levels and Typically, acute HAE mani- edema, result in varying degrees of in- function are normal has been de- fests as marked diffuse edema involv- testinal obstruction. Thus, typical scribed, so far only in women.2 ing all skin layers and layers of the symptoms of gastrointestinal tract in- All types of HAE have identical walls of hollow visceral organs and volvement are anorexia, vomiting, symptoms characterized by edema of solid organs. Most visceral organs are and crampy abdominal pain that can 1 or several organ systems. The skin, susceptible and can be affected sin- be severe. The abdomen is typically gastrointestinal tract, and respira- gly or in any combination. Typical at- tender to palpation, usually without tory tract are most commonly in- tacks of angioedema last approxi- guarding. Ascites, as a result of fluid volved. Cutaneous angioedema in- mately 2 to 5 days before resolving extravasation into the peritoneal cav- volves deeper layers such as the inner spontaneously. Skin edema is non- ity, occurs occasionally. In one dermis and subcutaneous tissue, un- pitting, with ill-defined margins, and study,12 ascites from acute HAE was like urticaria, which is common in most commonly affects areas of the significant enough to cause hypovo- angioedema from other causes and face, extremities, and genitals. Fa- lemic shock; however, the concomi- involves the epidermis and upper der- cial areas typically involved are the tant vasodilation known to occur dur- mis. The absence of pruritus, and the lips, eyelids, and tongue. More of- ing acute exacerbations probably often-present associated visceral ten, genital edema occurs as a result played an additive role. Diarrhea can symptoms, makes angioedema dis- of trauma during intercourse, partu- also occur, particularly as the acute tinguishable from urticaria. rition, and even horseback riding.8,9 episode resolves. Gastrointestinal tract During acute attacks, patients may HAE presenting as severe cramps, HISTORY OF HAE develop a rash similar to that seen in nausea, and vomiting, and unaccom- urticaria. Unlike urticaria, however, panied by cutaneous symptoms, can J. L. Milton first described angio- the skin lesions associated with HAE be mistaken for an acute abdomen. edema in 1876.3 The subsequent ar- are erythematous but not warm, pain- This occasionally leads to unneces- ticle by Quincke in 18824 was the first ful, or pruritic. sary surgical abdominal exploration to assign the name angioneurotic When edema occurs in the walls and the excision of otherwise nor- edema to the disease. A review of the of the respiratory and gastrointesti- mal gallbladders and appendixes. In literature suggests that the word neu- nal tract systems, the most ominous fact, without a high index of suspi- rotic was used as part of the name in and distressing symptoms of HAE oc- cion, gastrointestinal tract HAE may an attempt to describe the observed cur. Thus, laryngeal, nasal, and si- be undiagnosed for decades despite effect of mental stress on exacerba- nus edema may lead to respiratory patients presenting repeatedly to the tions of this disease. In 1888, Wil- tract compromise and death from suf- emergency department with these liam Osler5 published the first ar- focation. In such circumstances, tra- complaints. In such circumstances, ticle describing a hereditary form of cheostomy can be lifesaving because symptoms have occasionally been at- angioneurotic edema; however, dis- the edema associated with acute epi- tributed to psychosomatization, with covery of the biochemical basis for the sodes typically occurs at, or above, the patients inappropriately referred for disease did not occur until several de- larynx. If undiagnosed, mortality from psychiatric assessment. Attacks of gas- cades later. A seminal study pub- HAE can be as high as 30% to 40%, trointestinal tract angioedema gener- lished in 1963 by Donaldson and mostly due to upper airway obstruc- ally subside within 12 to 24 hours, Evans6 first described the biochemi- tion.10,11 Even in those with known whereas cutaneous angioedema per- cal abnormality responsible for HAE: HAE, unnecessary delay in seeking or sists for several days.13 the absence of C1-INH in patients administering appropriate medical Two case reports14,15 describe with the disease. Since that study, the treatment has often resulted in as- migrainelike and transient ische- body of knowledge regarding the phyxiation. Asphyxiation can occur mic attack symptoms during acute clinical manifestations, spectrum, at any age and has been documented HAE. Others9,16,17 have reported sei-

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 zures and hemiparesis. These symp- gioedema of an extremity as the first this factor. In general, the direct in- toms are thought to be caused by lo- presenting sign of the disease. Re- hibitory effect of C1-INH is achieved cal cerebral edema and consequent current abdominal pain and upper by the formation of irreversible co- cerebral hypoperfusion, caused by airway and facial edema occurred in valent bonds with these substrates, the acute HAE episode. 52% and 36%, respectively, of pa- forming inactive C1-INH com- Fever and leukocytosis are un- tients in one series.9 In 39% of these plexes. usual in acute HAE, and their pres- cases, patients could attribute their To facilitate a clear understand- ence during an attack in a person first episode to an identifiable trau- ing of the role of C1-INH in the in- known to have HAE should raise matic event.9 activation of its various substrates, suspicion that another process, such Most patients with symptom- brief reviews of the classical path- as infection or intra-abdominal ca- atic untreated HAE experience at way of complement activation and tastrophe, may be the inciting event least 1 acute exacerbation per month, of the contact (kallikrein/kinin) sys- for the acute exacerbation. and because each attack typically tem are necessary. Pregnancy has been associ- lasts a few days before spontane- ated with a decrease in serum C1- ously subsiding, it is estimated that The Complement Cascade INH levels, even in women with no individual patients can be debili- genetic evidence of HAE,18,19 but tated by their symptoms for 20 to Nine complement components (C1- pregnancy does not increase the risk 100 days per year.3 C9), and 2 pathways of comple- of attacks. In fact, pregnancy has of- ment activation (classical and alter- ten been associated with decreased PATHOPHYSIOLOGIC AND native) have been described. C1 attack frequency.9 These counterin- IMMUNOLOGIC FEATURES OF complement is a trimolecular het- tuitive observations may be ex- TYPES 1 AND 2 HAE eropentameric complex composed of plained by the finding that the total 1 C1q, 2 C1r, and 2 C1s compo- ␣ 28 amount of circulating C1-INH ac- C1 esterase inhibitor, an 2-glob- nents, all of which are linked tually increases during pregnancy; ulin of approximately 105 kd, be- through calcium molecules. In the however, a decrease in the measur- longs to the serine protease inhibi- classical pathway, interaction be- ␣ able level occurs as a consequence tor family that includes 1 - tween the immunoglobulin Fab frag- of the significant physiologic in- antitrypsin and antithrombin. It is ment and its target antigen results crease in plasma volume that oc- encoded on chromosome 11 and is in complement activation, initiated curs concomitantly.18 A study20 of synthesized mainly by hepato- through the binding of C1q to the one kindred with HAE suggested cytes, although peripheral blood constant heavy regions of the im- that significantly more pregnant pa- monocytes can also synthesize sig- munoglobulin Fc fragment. C1r is tients with HAE (60%) experi- nificant quantities. Skin fibroblasts subsequently recruited, and com- enced premature labor than did have also been shown to synthesize plexes first with bound C1q and then pregnant family members without this protein, but their contribution with C1s. This binding activates C1s, HAE; however, a causal relation- to the body’s pool of C1-INH in which acquires esterase activity and ship has not been established. Lev- physiologic circumstances in vivo is cleaves C4, thereby initiating a cas- els of C1-INH are also decreased fur- unknown.25 Cytokines, particu- cade of events that generates a com- ther in some pregnant women with larly interferon ␥, can stimulate syn- plex of complement fragments preeclampsia and eclampsia, and the thesis of C1-INH in these cells in termed the membrane attack com- role of low C1-INH levels in these vitro.25 Interleukin 6, an important plex. This complex is responsible for conditions is currently being inves- proinflammatory cytokine, in- the cell membrane damage that re- tigated.19,21 Increased attack fre- creases the release of C1-INH from sults in lysis of cells targeted by the quency has been reported22 in asso- HepG2 hepatoma cells in vitro. This specific immunoglobulins. During ciation with menstruation and oral action was potentiated by the pres- this cascade, C3a, C4a, and C5a are contraceptive use. ence of another proinflammatory generated, cause increased capil- cytokine, interleukin 1, which by lary permeability, and contribute to EPIDEMIOLOGIC itself has no effect on C1-INH syn- edema and swelling of skin and or- CHARACTERISTICS thesis or secretion.26,27 Thus, C1- gans that may be seen with massive INH synthesis in vivo can be regu- complement activation, as occurs Data on the epidemiologic charac- lated, at least in part, by these during an attack of HAE (Figure 1). teristics of HAE are sparse. Esti- cytokines. In humans, it is believed that mates of its incidence worldwide The major functions of C1- circulating C1 can undergo autoac- vary, from 1 in 1000023 to1in INH within the human body in- tivation and that it does so in in- 150000 persons.24 Types 1 and 2 clude the prevention of C1 comple- creasing quantities when C1-INH is HAE have been reported in all races, ment autoactivation; inactivation of insufficient or absent. A discussion and no sex predominance has been coagulation factors XIIa, XIIf, and of evidence for such autoactivation found. However, a recently de- XIa; and direct inhibition of acti- is beyond the scope of this review; scribed third type of inherited an- vated kallikrein.22 Its role in factor however, several detailed articles gioedema has been found only in XIa inactivation is a minor one, how- have been written on the sub- 2 ␣ 22,25,29-32 women. Seventy-five percent of pa- ever, with 1-antitrypsin being pri- ject. C1 esterase inhibitor tients with HAE have cutaneous an- marily responsible for inactivating prevents this autoactivation of C1

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 C4 C2 C3 C5 Trauma Prekallikrein

Factor XIIa C6-C9 Plasmin Activated C1

C4b2a3b5b C1 Esterase Inhibitor C1 Esterase Inhibitor Kallikrein C4a, C3a, and C5a

MAC High-Molecular-Weight Kininogen Bradykinin

Increased Capillary Permeability, Vasodilation, Nonvascular Smooth Fluid Extravasation, and Edema Muscle Contraction, and Edema

Figure 1. C1 esterase inhibitor prevents autoactivation of complement Figure 2. C1 esterase inhibitor inactivates factors XIIa and XIIf, plasmin, and component C1, thus keeping the classic complement pathway quiescent. kallikrein, thus preventing bradykinin production. MAC indicates membrane attack complex.

complement by causing dissocia- XIIa and XIIf result in an increasing fibrin breakdown, plasmin also acti- tion of the C1q subunit and by form- positive feedback loop, with factor vates factor XII, cleaves prekal- ing an inactive C1r2-C1s2-(C1- XIIa cleaving and activating further likrein to produce even more kal- 22,25 INH)2 complex. This complex molecules of factor XII. Because likrein, and activates C1 (Figure 3). is unable to cleave and activate C1-INH is the major inhibitor of At the tissue level, plasmin activity complement components C4 and factor XIIa, a decrease in its level may play a role in acute exacerba- C2, the usual substrates of acti- and activity allows generation of tions of HAE; however, its role in vated C1, thus keeping the classi- significantly increased quantities of plasma is probably short-lived be- ␣ cal pathway quiescent (Figure 1). factors XIIa and XIIf. Trauma, such cause of its rapid inactivation by 2- ␣ as that seen during surgery and antiplasmin and 2-macroglobulin, The Contact dental manipulation, also exposes its major inhibitors in plasma.22 (Kallikrein-Kinin) System large areas of negatively charged Factor XIIf activates comple- tissue and endothelial surfaces, ment component C1, thus initiat- Results of quantitative kinetic ex- which also results in activation of ing the classic pathway. Together periments32,33 suggest that C1-INH circulating factor XII.9 with the constant autoactivation of activity is responsible for inactivat- Factor XIIa also cleaves prekal- complement component C1 that oc- ing approximately 90% of factor XIIa likrein to the active enzyme kal- curs unchecked when C1-INH ac- and its metabolite factor XIIf likrein. Kallikrein in turn cleaves tivity is subnormal, activation and (Figure 2). Approximately 42% of high-molecular-weight plasma ki- consumption of C4 and C2 occur plasma kallikrein is inactivated by ninogens, resulting in excessive re- during acute HAE attacks, result- C1-INH activity,22 approximately lease of various kinins, especially ing in profoundly decreased serum ␣ 50% is inactivated by 2-macro- bradykinin and kallidin. Subnor- levels. Levels of C4, and sometimes globulin, and the remaining 8% is mal C1-INH activity also results in C2, are typically less than normal inactivated by other minor inhibi- loss of its direct inhibitory effect on during symptomatic quiescence, tors. kallikrein activity, thus further pro- showing ongoing low-grade con- Inactive precursor compo- moting bradykinin generation. The sumption between attacks; how- nents of the contact system include large quantity of bradykinin re- ever, these levels may return to high-molecular-weight kininogen leased during acute attacks of HAE normal in some patients between at- and prekallikrein. Factor XII is or AAE is thought to be respon- tacks.9,24,34 technically not a component of the sible for most symptoms by di- Recent studies35-38 have shown contact system, but it plays a sig- rectly causing increased vascular per- that bradykinin, not a C2 kininlike nificant role in its activation. It is meability (edema, swelling, and peptide, is responsible for most of hypothesized that in healthy indi- ascites), vasodilation (congestion, the symptoms of acute HAE (Fig- viduals, small quantities of factor erythema, and hypotension), and ure 2). Supporting data include the XII are constantly autoactivated to contraction of nonvascular smooth following: (1) large amounts of ac- factor XIIa, possibly by a multitude muscle (cramps, spasms, and pain). tivated kallikrein are present in in- of contacts between circulating fac- By increasing capillary permeabil- duced blister fluids of patients with tor XII and negatively charged ini- ity, C3a, C4a, and C5a may also con- HAE39; (2) levels of prekallikrein and tiator surfaces within the body.33 tribute to local edema of skin and high-molecular-weight kininogen Factor XIIa is cleaved during its visceral organs, ascites, and intra- are decreased during acute HAE ex- metabolism to another active mol- vascular volume depletion. acerbations40; (3) plasma bradyki- ecule, termed factor XIIf. Unop- Kallikrein also cleaves plasmino- nin levels increase significantly in posed activation of even small gen to the active enzyme plasmin. In persons with acute HAE and in those quantities of factor XII to factors addition to its better-known role of experiencing ACE inhibitor therapy–

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 Trauma Factor XII Autoactivation

XIIf

Factor XIIa C4

C1a

Plasmin

C4b C4a

Prekallikrein C4b2a C2

Kallikrein C2b C4b2a3b C3

HMWK

C3a

Plasminogen C4b2a3b5b

C5a

Bradykinin C6-C9 MAC

• Vasodilation • Increased Capillary • Nonvascular Smooth Permeability, Fluid Muscle Contraction Extravasation, and Edema

Figure 3. C1 esterase inhibitor modulates complement and contact (kallikrein-kinin) system activation, thus preventing bradykinin release and symptoms of hereditary angioedema. HMWK indicates high-molecular-weight kininogen; MAC, membrane attack complex.

related angioedema35; and (4) ve- mediated primarily by bradykinin. severe manifestations of systemic lu- nous blood bradykinin levels were This explains why patients with pus erythematosus overall, skin le- significantly higher in samples taken acute HAE typically have no urti- sions are prominent.46 In one study,45 from the affected vs unaffected arm caria. However, urinary histamine approximately 12% of patients with of patients with localized HAE ex- excretion is increased in 18% of pa- HAE had an associated autoim- acerbation.36 tients with acute HAE, suggesting in- mune disorder. This high propor- Typical HAE attacks usually creased systemic histamine release tion mainly comprises arthritides, subside spontaneously after 2 to 5 during this process.41,42 Comple- thyroiditis, glomerulonephritis, and days. However, the risk of death ment fragments C3a, C4a, and C5a, inflammatory bowel disease, all of from a vicious cycle of bradykinin and small fragments of C2 and bra- which have been reported to occur and complement fragment produc- dykinin, all of which are produced at a greater incidence in these pa- tion exists during every acute epi- in large quantities during acute HAE tients. Rarely, Sjo¨ gren syndrome, sode until appropriate therapy is ad- attacks, can cause mast cell degranu- drug-induced lupus, pernicious ane- ministered to raise serum levels of lation.23 Although total levels of mia, scleroderma, and autoim- active C1-INH or until spontane- complement component C3 usu- mune aortitis have also been asso- ous remission occurs. Spontaneous ally remain normal during attacks, ciated with the disease.9,20,45 remission may occur because the its turnover is increased (Figure 3).43 rapid consumption of various sub- VARIANT (“TYPE 3”) HAE strates during the acute attack rap- ASSOCIATED DISEASES idly outstrips the body’s ability to A recent German study2 described manufacture them. Patients with HAE have an in- recurrent angioedema in 10 female In patients with angioedema creased incidence of autoimmune probands and 26 of their female rela- from causes other than heredity, ur- diseases. An estimated 2% of pa- tives in the setting of normal C1- ticaria is a frequent accompanying tients also have systemic lupus ery- INH level and function. These pa- symptom. Urticaria seems to be pri- thematosus.44,45 This association has tients all manifested symptoms marily a histamine-mediated event, a strong female preponderance and, indistinguishable from types 1 and whereas angioedema seems to be although patients seem to have less 2 HAE, such as recurring skin le-

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 sions, abdominal cramps, and laryn- sequences.47,48 Hereditary angio- The exact chromosomal abnor- geal edema. Eighteen (50%) of these edema has an autosomal dominant mality responsible for the recently women had experienced at least 1 pattern of inheritance, although it is described inherited variant, in which episode of laryngeal edema, whereas estimated that 20% to 25% of cases recurrent angioedema occurs in fe- 15 had experienced multiple epi- are the result of spontaneous muta- males with normal C1-INH and C4 sodes (range, 2-200 episodes). Three tions in persons with no family his- levels and function, is unknown.2 No of the women died of asphyxiation. tory of the disease.49,50 All patients affected males were identified, and Age at onset varied widely, but most described in the literature have been these women came from 10 differ- patients developed initial symp- heterozygotes. Thus, by mendelian ent families, with 2 to 7 members af- toms in their second decade of life, inheritance, affected individuals in- fected in each family. Findings from as in the better-known types 1 and herit one normal gene and one ab- pedigree studies2 of these families 2 HAE. Twenty-two (61%) of pa- normal gene, and a child of an af- suggest an X-linked–dominant pat- tients developed initial symptoms fected patient has a 50% chance of tern of transmission; on occasion, between ages 10 and 23 years, and acquiring the abnormal allele. The the disease would skip one genera- 7 (19%) developed symptoms be- abnormal gene is either nonfunc- tion of females and affect the sub- tween 1 and 10 years of age. Like tional and thus is not transcribed sequent generation. Thus, the HAE, acute exacerbations of this (type 1 HAE) or codes for the syn- asymptomatic daughter of an af- variant have been linked to oral con- thesis of normal quantities of an ab- fected woman may give birth to fe- traceptive use (10 patients [28%]). normal C1-INH protein (type 2 male offspring who ultimately mani- In patients with this variant, HAE). fest the disease. C1-INH level and function and C4 Type 1 HAE is caused by a va- Phenotypically, type 1 HAE levels are normal during active an- riety of mutations with deletions or manifests as subnormal C1-INH lev- gioedema and when asymptom- insertions of single or multiple els, as low as 5% to 30% of normal, atic. This variant most likely repre- nucleotides in the C1INH gene, with resultant decreased activity.22 sents a congenital deficiency of whereas type 2 HAE results from the Type 2 HAE results in synthesis of enzymes such as ACE, carboxypep- synthesis of a dysfunctional C1- normal and mutant protein. The C1- ␣ tidase N, and 2-macroglobulin or INH protein, usually caused by point INH functional activity of the mu- a phenotypic decrease in the func- mutations in the areas coding for the tant protein is impaired despite the tion of these enzymes. Another pos- “reactive center” or “hinge region” presence of normal or supranormal sibility is that these individuals pro- of the C1-INH protein.51,52 The re- serum levels. Because patients with duce an as yet unknown substance active center of C1-INH is the site type 2 HAE possess one normal and that is not regulated by C1-INH and that binds and cleaves target mol- one abnormal allele, theoretically that is capable of cleaving large quan- ecules. It is located at the Arg444- their pool of C1-INH should con- tities of high-molecular-weight ki- Thr445 site of the C1-INH mol- sist of 50% normal protein and 50% ninogen to produce bradykinin. Be- ecule and requires an intact peptide mutant protein. However, it has been cause C1-INH exerts inhibitory bond between these 2 amino acids found that levels of normal C1- actions on kallikrein and factors XIIa for proper function.25 Some muta- INH protein in these patients are and XIIf and because C1-INH lev- tions in the C1INH gene result in typically far below 50% (range, 5%- els are normal in these patients, the substitutions at Arg444 of the C1- 30%), despite evidence that synthe- physiological defect responsible for INH protein, and such mutations sis of this normal protein in these pa- angioedema in these patients is have been estimated to account for tients occurs at approximately half probably downstream of kallikrein up to 70% of those with type 2 the rate seen in individuals without (Figure 3). HAE.51-53 Such mutations result in an HAE.56 Such low levels are thought The absence of detectable ab- amino acid change, from arginine to to occur because the single normal normalities in C1-INH level or func- others such as cysteine or histidine allele cannot increase synthesis of tion, or in C4 levels, even during at position 444. Other mutations normal C1-INH to a rate necessary acute exacerbations of angio- within the reactive loop, but dis- to keep pace with its consump- edema, makes it likely that this en- tant from the reactive center, have tion.22 The finding that the frac- tity will receive its own unique no- been described. One such muta- tional catabolic rate of normal C1- menclature. So far, the defect has tion in a patient with type 2 HAE re- INH is increased by approximately been found only in women, suggest- sulted in the substitution of threo- 29% in patients with HAE lends sup- ing an X-linked–dominant pattern of nine for alanine at position 436 of port to this hypothesis.56,57 inheritance, and X-linked angio- the C1-INH molecule.54 To date, edema may be an appropriate name. more than 100 different C1-INH mu- ACQUIRED ANGIOEDEMA tations have been identified in pa- GENETICS OF HAE tients with HAE, and their varied ef- Acute attacks of angioedema can also fects on C1-INH protein synthesis occur because of the acquired form The gene encoding C1-INH has been and function may explain the ob- of the disease. Acquired angio- cloned. It is located on chromo- served clinical differences in dis- edema results from increased de- some 11q11-q13.1, possesses 7 ex- ease severity in affected individu- struction or metabolism of C1- ons and approximately 7 introns, als.51,55 Homozygous C1-INH INH. Patients with AAE do not have and contains multiple Alu repeat deficiency has not been described. the genetic mutations of HAE. Typi-

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 cally, the first exacerbations of HAE dissociates from the C1-INH rem- in healthy individuals, including an- occur during the second decade of nant to which it was bound and pro- tibiotics, narcotic and nonsteroidal life or earlier, whereas AAE usually ceeds to bind with a fresh 105-kd analgesics, angiotensin II inhibi- becomes symptomatic during or af- C1-INH molecule. Thus, low levels tors (losartan potassium), and ACE ter the fourth decade. of autoantibody can result in inac- inhibitors. Allergic phenomena seem Two types of AAE have been tivation of large quantities of C1- to play a major role in all except ACE described. Type 1 AAE typically oc- INH.13 Analysis of autoantibodies to inhibitor therapy–related angio- curs in patients with rheumato- C1-INH has shown that patients pro- edema. Although allergic and im- logic disorders and B-cell lympho- duce antibodies that recognize dif- munologic mechanisms, such as the proliferative diseases, including ferent epitopes within the C1-INH “hapten hypothesis” in the case of leukemia (chronic lymphocytic leu- molecule. captopril, have been proposed to kemia), lymphosarcoma, multiple As described earlier in the sec- explain ACE inhibitor therapy– myeloma, macroglobulinemia, and tion “The Complement Cascade,” related angioedema, they do not ex- essential cryoglobulinemia.22 Rarely, small amounts of C1 complement plain the constellation of manifes- it has been reported in association autoactivate on a continuous basis tations and laboratory findings seen with carcinomas (rectal, gastric, and in humans. In unaffected individu- in this condition. Urticaria, which breast), lupus anticoagulant, Churg- als, normal levels of C1-INH inac- sometimes occurs concomitantly in Strauss vasculitis, erythrocyte sen- tivate these molecules and prevent ACE inhibitor therapy–related an- sitization, livedo reticularis, infec- full activation of the classic comple- gioedema, is more aptly explained tions (human immunodeficiency ment pathway. However, in pa- by the hapten hypothesis than is an- virus, hepatitis C virus, hepatitis B tients with AAE, in whom C1-INH gioedema. virus, Echinococcus granulosus, and levels are already significantly Most of the structurally di- Helicobacter pylori), and, in one in- decreased via consumption or in- verse ACE inhibitors on the market stance, T-cell lymphoma.13,58-60 These activation, C1-INH is further con- have been reported to cause angio- patients have circulating anti- sumed as it performs its housekeep- edema (Table 1).1 Angiotensin- idiotypic antibodies against spe- ing functions, including inactivation converting enzyme has 2 main cific immunoglobulins expressed on of autoactivated C1. In fact, the frac- substrates in the human body, an- the surface of B cells. Thus, im- tional catabolic rate of C1-INH in pa- giotensin I and bradykinin, which it mune complexes are continually tients with AAE is more than twice cleaves into smaller molecules. In the being formed between anti- that seen in unaffected individuals case of bradykinin, this cleavage in- 73 idiotypic antibodies and surface im- and approximately 11⁄2 times that in activates the molecule. Because bra- munoglobulins on the cell surface, individuals with HAE.57 dykinin excess has been implicated and these complexes in turn are Patients with AAE have signifi- at the tissue level in HAE, ACE in- thought to continuously activate cantly decreased serum levels of clas- hibitors may induce angioedema in complement component C1. C1 es- sic complement components, par- susceptible individuals by causing terase inhibitor is consumed as it in- ticularly C1q, C4, and C2. In bradykinin accumulation with re- activates these large quantities of C1, particular, decreased serum C1q lev- sultant vasodilation, capillary leak- and, ultimately, because C1-INH els help distinguish AAE from HAE, age, and edema. synthesis cannot keep up with its in which C1q levels are usually nor- Angiotensin-converting en- consumption, levels decline below mal. The decreased C1q levels seen zyme, also called kininase II, is normal, setting the stage for acute in AAE but not in HAE reflect the widely distributed in the human attacks of angioedema. central role of C1 autoactivation and body. It is still unclear why only a In type 2 AAE, autoantibodies consumption in driving the symp- few individuals develop angio- (typically IgG and sometimes IgA or toms of AAE via C1-INH depletion edema from ACE inhibitor therapy, IgM) directed against the C1-INH and consequent contact system au- whereas most do not. Patients who molecule are produced and re- toactivation. develop angioedema while taking an leased into the patient’s circula- A 12% prevalence of autoanti- ACE inhibitor may be those with a tion. These bind the active site of the bodies to C1-INH has also been re- congenital or acquired impairment C1-INH molecule, leading to its in- ported in patients with liver cirrho- in carboxypeptidase N activity (also activation.35,61,62 After inactivation of sis.63 Although these patients had called kininase I, which degrades the normal 105-kd C1-INH mol- significantly lower quantitative C1- bradykinin), which would lead to ecule through binding with autoan- INH levels than those without au- significant accumulation of brady- tibody, an inactive 96-kd C1-INH toantibodies, they did not develop kinin once ACE activity is blocked.74 fragment is cleaved from the bound acute angioedema. Use of ACE inhibitors has been C1-INH molecule and circulates in associated with angioedema in ap- the patient’s blood, where it can be ACE INHIBITOR proximately 0.1% to 0.5% of measured. This fragment can lead to THERAPY–INDUCED cases.1,75,76 No sex predominance has the finding of “normal” C1-INH lev- ANGIOEDEMA been noted in patients without gas- els on some laboratory assays, in the trointestinal tract involvement. In setting of markedly attenuated C1- A variety of commonly prescribed contrast, all patients described in the INH activity. Once the 96-kd frag- medications have been associated literature of ACE inhibitor therapy– ment is cleaved, the autoantibody with the occurrence of angioedema associated angioedema in whom gas-

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 mine2 receptor antagonists seems to Table 1. Cases of Gastrointestinal Tract Angioedema provide additional relief in a few pa- Related to Angiotensin-Converting Enzyme (ACE) Inhibitor Therapy tients. If use of antihistamines does in the English-Language Literature* not provide symptomatic control, Duration of ACE corticosteroids may be adminis- Inhibitor Use Before tered. The details of management of Study ACE Inhibitor Symptom Onset Method of Diagnosis CIA are well documented23,78 but are Chase et al64 Lisinopril 1 mo Abdominal CT scan beyond the scope of this review. Byrne et al65 Fosinopril sodium 3 d Clinical examination Patients with CIA, particu- Byrne et al65 Lisinopril 2 y Laparotomy larly those with frequent and per- Farraye et al66 Enalapril maleate 12 h Small-bowel radiography sistent episodes, should undergo an- 67 Mullins et al Enalapril maleate Not specified Small-bowel radiography and nual general medical evaluation to laparotomy Abdelmalek and Lisinopril 48 h Small-bowel radiography, investigate for any underlying oc- Douglas68 abdominal CT scan, and US cult disease. Matsumura et al69 Captopril 2 d Abdominal US Jacobs et al70 Enalapril maleate 9 wk Small-bowel radiography DIAGNOSIS Guy et al71 Lisinopril 4 mo Laparoscopy and US Gregory and Lisinopril Not specified Abdominal CT scan Hereditary angioedema is transmit- Davis72 ted in an autosomal dominant pat- *CT indicates computed tomographic; US, ultrasonography. tern, and the parents, siblings, and offspring of patients with HAE should be tested and receive ge- trointestinal tract involvement has inhibitors trigger attacks when taken netic counseling. Some individuals occurred have been women.64 This by individuals with HAE. with biochemical findings consis- has led to speculation about a pos- Treatment consists of discon- tent with HAE never experience an sible sex-linked susceptibility to gas- tinuing use of the ACE inhibitor. An- acute exacerbation of the disease.79 trointestinal tract involvement. tihistamines, anticholinergics, and We80 described a patient with HAE Although the onset of angio- corticosteroids are useful when whose 53-year-old father was asymp- edema typically occurs during the urticaria occurs with angioedema tomatic despite having decreased first week of therapy with these but are ineffective if use of the ACE C1-INH function (37%) in the set- agents, symptoms have occurred as inhibitor is continued.67 Subcuta- ting of normal serum levels. Other long as 2 to 3 years after the first neous (1:1000 mixture) and nebu- patients do not manifest symptoms medication use.1,65 Symptoms re- lized epinephrine should be admin- of the disease until as old as 70 solve within 24 to 48 hours of dis- istered in cases in which the airway years.23 In 20% to 25% of patients continuing the drug therapy and is threatened, as outlined in the with HAE, there is no family his- typically recur on rechallenge with “Management” section. tory of the disease.16,49,50,79 There- the same, or another, ACE inhibi- fore, a positive family history of HAE tor. Upper airway obstruction rarely CHRONIC IDIOPATHIC is not a prerequisite for consider- occurs in patients with angio- ANGIOEDEMA ation of HAE in the differential di- edema secondary to ACE inhibitor agnosis when typical symptoms are use. One study77 has proposed that In some instances, chronic recur- present. previous upper airway trauma, in- rent angioedema cannot be attrib- In the patient with suspected strumentation, or manipulation may uted to HAE, AAE, or any of the HAE who is currently asymptom- represent a risk factor for develop- known drug-induced and physical atic, serum C1-INH activity should ing such upper airway obstruction causes. Patients with such symp- be measured. If this is subnormal, secondary to ACE inhibitor therapy– toms have been deemed to have then quantitation of C1-INH and related angioedema. chronic idiopathic angioedema C1q levels will help distinguish be- Findings on physical examina- (CIA). This is an important differ- tween HAE and AAE.3 Patients with tion and radiologic testing are simi- ential diagnosis for such patients, be- HAE will have markedly decreased lar to those seen in HAE. However, cause its management differs from C1-INH activity and normal C1q lev- unlike in HAE, a mild to moderate that for HAE. In most instances, els, with decreased (type 1), nor- leukocytosis has been noted in some chronic urticaria is also present. The mal, or supranormal (type 2) levels studies64,66-68 of ACE inhibitor thera- clinical presentations of CIA and of C1-INH. Those with AAE will also py–related angioedema. HAE are similar, but pruritus typi- show a marked decrease in C1- Angioedema resulting from cally accompanies CIA and laryn- INH activity; however, C1q levels are ACE inhibitor use can be distin- geal edema is rare. concomitantly decreased below nor- guished from HAE and AAE only by Antihistamines and, in severe mal (Table 2). history, C1-INH levels, and comple- or refractory cases, corticosteroids During an acute presentation of ment assays. Most patients who de- are the mainstay of therapy. Hista- symptoms consistent with HAE, C4 velop ACE inhibitor use–related an- mine1 receptor antagonists provide and C2 levels are markedly de- gioedema have normal C1-INH symptomatic relief in most increased, sometimes to undetect- levels and function. However, ACE stances, but the addition of hista- able levels, and therefore are useful

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 Table 2. Classification and Distinguishing Features of Hereditary and Acquired Angioedema*

Hereditary Angioedema Acquired Angioedema

New Variant Type 1 Type 2 “Type 3” Type 1 Type 2 Typical age at presentation Infancy to second Infancy to second Ͻ1-63 y Ն40 y Ն40 y decade of life decade of life C1-INH level ↓ Normal or ↑ Normal ↓ “Normal” or ↓ C1-INH activity ↓↓ Normal ↓↓ Serum C4 level ↓↓ Normal ↓↓ Serum C1q level Normal Normal Normal ↓↓ Mode of transmission AD AD X-linked NA NA Sex predominance No No F Ͼ MNo No Efficacy of C1-INH concentrate Yes Yes No Yes Yes Efficacy of attenuated androgens Yes Yes Unclear Yes No Efficacy of antifibrinolytic agents Yes (all) Yes (all) No Yes (⑀-aminocaproic Yes (⑀-aminocaproic acid) acid)

*C1-INH indicates C1 esterase inhibitor; ↓, decreased; ↑, increased; AD, autosomal dominant; NA, not applicable; and all, ⑀-aminocaproic acid and tranexamic acid.

confirmatory tests. Complement is angioedema, including drugs, food els) and small-bowel thickening, chronically consumed in patients allergens, and environmental and respectively. “Thumbprinting” and with HAE even between exacerba- topical allergens. a stacked coin appearance, also tions, albeit at a much slower rate Patients with acute gastroin- signs of mucosal edema, may also than that seen in acute exacerba- testinal tract HAE have been inad- be seen on radiographs. Mild or tions. The C4 level is persistently low vertently subjected to endoscopy moderate ascites, which resolves in most, but not all, patients, whereas when the diagnosis is unknown. Any after the acute attack, may also be the C2 level may remain decreased instrumentation of the oropharynx seen on ultrasound.79 Patients typi- in a smaller proportion of patients. is relatively contraindicated when cally are afebrile and have normal In a few patients, C4 and C2 levels acute HAE is considered the lead- liver enzyme, bilirubin, amylase, normalize in the absence of symp- ing differential diagnosis in a pa- and lipase levels during acute epi- toms.9,24,34 There is no correlation be- tient with acute abdominal pain sodes. White blood cell counts may tween the magnitude of decrease in because of the risk of inducing life- be normal or slightly elevated. C1-INH level or activity and the se- threatening laryngeal edema. If there Ultrastructurally, gaps in the verity or frequency of acute HAE are compelling reasons why upper postcapillary venule endothelial attacks. In newly symptomatic endoscopy should be done in this cells, as are typically seen with the middle-aged or older patients with circumstance, appropriate prophy- actions of vasoactive substances, are biochemical findings of HAE, C1q laxis, as described in the “Manage- seen in tissue from affected areas.78 quantitation should be performed to ment” section, is necessary. None- The resulting edema has minimal rule out AAE. theless, the endoscopic appearance cellularity. Heparinization, such as that at- of gastrointestinal tract HAE has tained during management of car- been described, with findings of dif- MANAGEMENT diac ischemia or cardiac bypass sur- fuse mucosal edema and erythema, gery, has been associated with with bulging masses of gastric mu- Although approximately a quarter of spuriously elevated C1-INH activ- cosa resembling a submucosal tu- HAE cases occur as a result of spon- ity.81 Thus, if C1-INH function is mor.82 All the gastric lesions had re- taneous mutations, most patients in- normal in a heparinized patient solved at second endoscopy 8 weeks herit the responsible mutation in an when the index of suspicion for HAE later. Similar lesions noted along the autosomal dominant pattern. Thus, is high, the C1-INH functional as- small intestine on imaging studies genetic counseling of affected indi- say should be repeated a week after are thought to be responsible for the viduals, as well as their parents and the discontinuation of heparin radiographic appearance and ob- siblings, is an important part of their therapy. structive symptoms seen during overall treatment. These relatives of Diagnosis of the recently de- acute attacks. the proband, as well as their off- scribed HAE variant in the setting of Stomach mucosal biopsy spring, should be tested after ge- recurrent angioedema requires a de- samples taken during attacks of netic counseling is completed. tailed personal and family history, HAE show moderate nonspecific Where available, the treatment pedigree analysis, and biochemical inflammatory cell infiltration and of choice for acute attacks of HAE or evidence of normal C4, C1q, and C1- edema of the lamina propria.82,83 AAE is intravenous purified, vapor- INH levels and function during Plain radiographs and computed heated C1 esterase inhibitor concen- symptomatic and asymptomatic tomographic scans of the abdomen trate. If this is unavailable, then at- periods. The personal history must typically show varying degrees of tenuated androgen administration rule out all other causes of isolated ileus (sometimes with air-fluid lev- (below) should be started immedi-

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 ately, particularly when there is up- some researchers86 have reported suc- age ranges for danazol, stanozolol, per airway involvement. After an cess in the acute management of AAE and methyltestosterone are 200 to infusion of C1 esterase inhibitor con- using these agents, probably owing 800 mg/d, 2 to 12 mg/d, and 10 to centrate, serum levels of C1-INH in- to control of the mast cell degranu- 30 mg/d, respectively. A typical treat- crease immediately, followed 2 to 24 lation and histamine release. Propo- ment regimen using the less expen- hours later by a slower increase in lev- nents of this therapy suggest ad- sive agent, stanozolol, is to start adult els of C4.84 A randomized, placebo- ministration of nebulized racemic patients at a dosage of 4 mg 3 times controlled trial84 of therapy with C1 epinephrine (1:1000 mixture) and daily for the initial 12 weeks, then esterase inhibitor for acute attacks of subcutaneous epinephrine (0.2-0.3 tapering the dosage by 2 to 4 mg ev- HAE found that approximately 69% mL of 1:1000 concentration admin- ery 12 weeks until the lowest main- of acute attacks treated with the con- istered every 20-30 minutes up to a tenance dose that provides symp- centrate responded completely within maximum of 3 doses).23 Administra- tomatic relief is reached (typically 30 minutes of the infusion, and up tion of epinephrine early in an at- 2-6 mg/d). An alternative approach to 95% of attacks responded within tack seems to produce better re- is to reduce the dosage as soon as 4 hours. In comparison, only 12% of sults. Symptomatic improvement has symptomatic control is achieved. those who received placebo had their been reported for type 2 AAE using Maintenance using alternate-day ad- attacks subside by 4 hours. Patients intravenous methylprednisolone, 500 ministration of stanozolol is also ef- who received C1 esterase inhibitor to 1000 mg daily.62 fective. The lowest effective dose concentrate were monitored for 4 Use of attenuated androgens should be used for maintenance. At- years after completion of the study, (17-␣ alkylated androgens), such as tenuated androgens are efficacious and none developed seroconversion danazol and stanozolol, can pre- in the prophylaxis of central ner- for any blood-borne viral infection vent symptomatic attacks in pa- vous system angioedema.15 Dana- (human immunodeficiency virus and tients with HAE. Some patients with zol doses as low as 200 mg every 2 hepatitis B and C). Also, none devel- AAE, particularly type 1 disease, also or 3 days have been used success- oped autoantibodies to C1-INH as a respond to administration of these fully to reduce attack frequency.62 result of the infusion of concen- agents. Patients with type 2 AAE When surgery, dental manipula- trate. Therapy with C1 esterase in- typically derive little benefit from tion, or another source of trauma is hibitor concentrate is thus consid- androgen therapy. Androgens in- planned, prophylactic treatment is ered safe and effective for the crease serum C1-INH, C4, and C2 necessary using danazol, 600 mg, management of acute HAE attacks. levels.87,88 Methyltestosterone ther- daily for 10 days before surgery, or Currently, C1 esterase inhibitor con- apy is effective in men. In an anec- equivalent doses of another andro- centrate is not available in the United dotal study,89 oxandrolone, a po- genic agent. States. tent androgen, was used successfully The major contraindications to C1 esterase inhibitor concen- as prophylaxis in a 13-year-old girl therapy with attenuated androgens trate, although recommended as the who had failed prophylactic therapy are pregnancy and lactation, pros- first line of therapy for acute AAE ex- with high-dose danazol and ⑀-ami- tate cancer, and childhood. Poten- acerbations, is not as effective for this nocaproic acid. The patient’s symp- tial adverse effects include increased condition as it is for HAE. The pres- toms were controlled with a daily hair growth, weight gain, seborrhea, ence of large amounts of anti–C1- dose approaching 7 mg.89 acne, deepening of the voice, vaso- INH autoantibodies, which rapidly Some authors90,91 suggest that motor symptoms, decreased breast inactivate infused C1 esterase in- long-term prophylaxis should be of- size, menstrual irregularities, de- hibitor concentrate in the serum of fered to patients with 1 or more acute creased libido, hepatic necrosis or patients with type 2 AAE, is thought exacerbations monthly. However, in cholestasis, hepatic neoplasms, hy- to be responsible for this decreased a recent study,11 5 of 6 patients with pertension, and possibly increased efficacy.85 For type 1 AAE, treat- HAE who asphyxiated had experi- atherogenesis resulting from abnor- ment of the underlying malig- enced no more than 3 exacerba- mal lipoprotein metabolism. Hepa- nancy, lymphoproliferative or rheu- tions per year. The risk of upper air- tocellular adenomas, and in one matologic, disorder may result in way involvement, with the attendant instance hepatocellular carcinoma, resolution of clinical and labora- risk of asphyxiation, is high with have been reported in patients tak- tory abnormalities.13 C1 esterase in- each attack regardless of which or- ing danazol for 10 or more years.92,93 hibitor concentrate was ineffective gan system was involved in previ- Abnormal liver enzyme levels, from in treating patients with the variant ous attacks. Long-term prophy- chronic hepatitis, have been shown inherited angioedema.2 laxis should be considered in any not to change significantly after ini- Intubation and ventilator sup- patient with a previous history of tiation of therapy with these agents port may be necessary for episodes acute HAE affecting any organ sys- and should therefore not be consid- associated with severe respiratory tem, regardless of the number of pre- ered an absolute contraindication to tract compromise from laryngeal vious attacks. their use.91 Stanozolol therapy seems edema. Most reports suggest that Attenuated androgens are used to have fewer adverse effects than does acute exacerbations of HAE or AAE in the long-term prophylactic treat- danazol therapy. Antiandrogens used typically do not respond to admin- ment of male and female patients be- in the treatment of prostate cancer istration of antihistamines, glucocor- cause they are effective and have may decrease the efficacy of these ticoids, or epinephrine. However, relatively mild adverse effects. Dos- therapies.

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Downloaded From: https://jamanetwork.com/ on 09/26/2021 Intravenous administration of edema. One patient responded to enterology, E19B, Mayo Clinic, 200 fresh frozen plasma (FFP), which danazol therapy, whereas another First St SW, Rochester, MN 55905. contains C1-esterase inhibitor, may did not. Use of antifibrinolytic agents 2 help abort most episodes of acute was also ineffective. REFERENCES HAE. However, a paradoxical exac- Cytotoxic and immunosuppres- sive therapy (typically with cyclo- erbation of symptoms occasionally 1. Hedner T, Samuelsson O, Lunde H, Lindholm L, occurs presumably because the ex- phosphamide) and glucocorticoid Andren L, Wiholm BE. Angioedema in relation cess C4 supplied in FFP acts as a sub- therapy, with or without plasmapha- to treatment with angiotensin converting en- strate that fuels further tissue dam- resis, are beneficial in decreasing au- zyme inhibitors. BMJ. 1992;304:941-946. age. Consequently, FFP infusion is toantibody production in type 2 2. 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C1-esterase inhibitor in uncomplicated preg- The use of antihistamines and Accepted for publication July 10, 2001. nancy and mild and moderate preeclampsia. epinephrine was ineffective in the Corresponding author: William Thromb Haemost. 1991;65:134-138. treatment of the variant angio- J. Tremaine, MD, Division of Gastro- 22. Davis AE. C1 inhibitor and hereditary angio-

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