Hereditary angioedema: a clinical review for the otolaryngologist.
Hereditary angioedema (HAE) is a relatively rare, potentially life-threatening condition caused by a genetic (autosomal dominant) deficiency of C 1 esterase inhibitor (C1-INH), a human plasma protein that regulates the contact (bradykinin-forming), complement, and fibrinolytic systems. HAE is characterized by marked, diffuse, nonpitting, nonpruritic edema, which is commonly confned to the extremities but which can also occur in the gastrointestinal tract, where it results in pain, nausea, and vomiting.
HAE is important to otolaryngologists because its most serious consequence is edema of the mucosa of the upper airway that can lead to severe airway obstruction and even death. It has been estimated that approximately 50% of patients with HAE may be expected to experience at least one laryngeal event in their lifetime. (1) If left undiagnosed or untreated, airway obstruction is asociated with mortality rates as high as 30%. (2) Moreover, the risk of death from asphyxiation is not limited to those with a history of laryngeal involvement. (3) HAE symptoms, particularly in cases where the airway and gastrointestinal tract are involved, are often severe enough to require hospitalization. Indeed, reports suggest that in the United States alone, HAE accounts for between 15,000 and 30,000 emergency department visits annually. (4)
As our understanding of the underlying pathology and biochemical defects associated with HAE has increased, it has been possible to develop effective preventive and acute treatment approaches, which should decrease the use of invasive interventions and reduce mortality in patients with more severe attacks. However, timely and accurate diagnosis of HAE remains challenging because of the lack of clinical experience among treating physicians, which can be attributed to the disease's relatively low prevalence, estimated to range from 1/10,000 to 1/50,000 population. (5) The diagnosis is often missed or delayed, especially in patients with no family history; the interval between symptom onset and diagnosis can exceed 20 years. (6)
This article aims to provide an overview of the pathologic features and clinical presentation of HAE, with a view toward improving the differential diagnosis and enhancing effective management.
Pathophysiologic and genetic defects
The clinical features of angioedema were first described by Milton in 1876. (7) Some 12 years later, Osler provided the first description of a hereditary form, which he initially called hereditary angio-neurotic oedema, reflecting the suggestion at the time that "nervous" influences were involved. (8) It was not until 1963 that Donaldson and Evans reported that the underlying biochemical defect was a deficiency of C1-INH. (9) C1-INH is a member of the serine protease inhibitor family, and it plays a role in regulating a number of major biochemical pathways. (10) It is the primary regulator of the classic complement pathway, and it inhibits key components of the contact (kallikrein-kinin) system, both of which are activated during attacks of HAE. Overwhelming evidence suggests that the symptoms of HAE are mainly the result of a deficiency in the regulation ofthelatter pathway. C1-INH regulates the actions of kallikrein, which cleaves high molecular-weight kininogen to generate bradykinin. Bradykinin has been shown to be responsible, via activation of the bradykinin [B.sub.2] receptor, for most of the physiologic changes that cause the acute symptoms of HAE; these changes include vasodilation, increased tissue permeability, and smooth-muscle contraction." The complement pathway, however, remains important in the understanding of HAE, as complement proteins such as C4 and Clq are key to laboratory testing and diagnosis (see section entitled, "Differential diagnosis"). A schema of the complement and contact systems, which illustrates the points of action of C1-INH, is shown in the figure.
As its name suggests, hereditary angioedema is an inherited disorder. It occurs as a result of a mutation in the gene that controls the production of C1-INH, which is located on chromosome 11 (11q12-q13.1). More than 200 mutations of the C1-INH gene have been described. (2) HAE is passed on in an autosomal dominant fashion, and thus the offspring of affected individuals have a 50% chance of being affected. Despite its name, however, it has been estimated that 20 to 25% of cases of "hereditary" angioedema occur as a result of spontaneous mutation, a fact that has implications for diagnosis. (2)
Two primary types of HAE have been described, which are called simply type I and type II (table 1 ). They cannot be distinguished on the basis of symptoms alone:
* In type I HAE, which accounts for about 80 to 85% of cases, the circulating C1-INH concentration is reduced because of mutations that alter effective gene transcription. (12)
* In type II HAE, which accounts for the other 15 to 20% of cases, the level of C1-INH secretion is relatively normal or even elevated, but the protein is biologically dysfunctional (i.e., <30% function). (12)
There have been reports of another type of inherited angioedema that is distinct from HAE types I and II and that occurs primarily in women. (13) This variant, described as inherited (or familial) angioedema with normal C1-INH (although it was previously known as type III HAE), does not occur as a result of a C1-INH deficiency but may involve abnormal factor XII expression (table 1).
Clinical picture of hereditary angioedema
A definitive diagnosis of HAE is difficult to achieve, and misdiagnosis is common. As mentioned, as many as 20 years can pass from the onset of symptoms to the final diagnosis. (6) This should not be too surprising, given the rarity of this disease and the similarity of its symptoms to those of other forms of angioedema. The ENT surgeon, faced with a patient presenting with life-threatening edema of the airway, must first establish an airway. Thereafter, an understanding of both the clinical picture and the underlying pathophysiologyis important in making the diagnosis and in determining appropriate future treatment options.
During an HAE attack, patients may experience a marked, diffuse, mucosal edema that is nonpitting. nonpruritic, and characteristically nonurticarial. The swelling typically develops gradually over several hours. It may resolve spontaneously over a period up to 7 days. Even mild attacks can be disfiguring and disabling. Most episodes involve skin swelling and abdominal symptoms. In fact, Bork et al found that 97% of affected patients reported episodes involving these two sites. (14) In that study, the authors used standardized questionnaires to document symptoms during 130,000 episodes in 221 patients and found that skin and abdominal attacks accounted for 50 and 48% of episodes, respectively. Among the patients who experienced skin swelling, 97.5% reported involvement of the extremities. Facial swelling was reported by 78% of patients, although this accounted for only 3.3% of episodes. More than 90% of the 221 patients reported recurrent abdominal attacks.
Painful gastric symptoms with associated nausea and vomiting are common in HAE,15 and it is not unknown for patients to undergo an appendectomy or laparotomy because these acute gastric symptoms were incorrectly identified as a surgical emergency? Potentially the most serious feature of this disease, however, is edema of the upper airway; in fact, asphyxiation is the most common cause of death in HAE. As was noted earlier, death from asphyxiation can occur even in patients who have no history of laryngeal involvement. (3)
Overall, the pattern of symptoms in HAE is considerably variable. The site of attack differs among patients--and sometimes even within the same patient. Moreover, the frequency of attacks ranges from rarely to weekly and even more frequently.
HAE typically manifests initially during the second decade of life, and it has is no known race or sex bias. Precipitating factors include infections, emotional stress, menstruation, and contraceptive use, as well as the use of certain medications. (12) Other known triggers are trauma and invasive medical procedures; reports in the literature have described severe laryngeal edema and even death from asphyxiation following routine tooth extraction. (1,16) However, many HAE attacks have no identifiable trigger.
A diagnosis of HAE is first suggested by a history of recurrent attacks of peripheral angioedema. Family history is a key component in the diagnosis, as most cases are inherited. However, as noted earlier, between 20 and 25% of cases arise as the result of a spontaneous mutation of the C1-INH gene, so a negative family history does not rule out a diagnosis of HAE. A full family history should include an investigation into whether there have been unexplained recurrent HAE episodes in children as well as parents.
Because HAE is characterized by a C1-INH deficiency, laboratory analysis of circulating complement components is a key diagnostic tool (table 1 ). Patients with type I HAE have low levels of circulating C1-INH and C4 proteins. The C4 level is a particularly sensitive indicator of HAE, so a normal C4 level is suggestive of a diagnosis other than HAE. If C4 levels are low and C1-INH levels are normal or elevated, tests for C1-INH function should be carried out; the presence of dysfunctional C1-INH protein (i.e., a functional C1-INH level <30%) points to a diagnosis of type II HAE. In all three forms of HAE, Clq levels are normal.
Forms of angioedema other than the hereditary variant include allergic angioedema, angiotensin-conver ting enzyme (ACE)-inhibitor-induced angioedema, acquired angioedema (types I and II), and chronic idiopathic angioedema (table 2). Their diagnosis is based on a combination of general features, including the patient's history, age, presenting symptoms, triggers, genetic components, and laboratory findings, in particular, analysis of circulating complement components in fresh or fresh frozen serum.
One distinguishing feature of HAE is the absence of urticaria, a condition that is often present in the other forms of angioedema. (17) It is worth noting, however, that as many as 25% of HAE patients may experience prodromal erythema marginatum, a generally painless and nonpruritic condition that can be mistaken for urticaria. (18)
Allergic angioedema. Mlergic angioedema is the most common form of angioedema. In affected patients, a classic histamine response is provoked by known triggers such as food, drugs, and bee stings. Urticaria is likely to be present. Complement protein assays show normal levels.
ACE-inhibitor-induced angioedema. Normal complement protein levels are also seen in ACE-inhibitor-induced angioedema, which is also more common than HAE, with an incidence reported to be around 0.1 to 0.2%. (17) Symptoms are not caused by an allergic response to the ACE inhibitor but by the drug's pharmacologic actions. The function of ACE is to cleave and inactivate two main substrates: angiotensin I and bradykinin. The blocking of ACE by inhibitor drugs therefore allows for an accumulation of bradykinin, which is the key mediator of angioedema. Therefore, ACE inhibitors are contraindicated in HAE patients. (19) Airway obstruction in ACE-inhibitor-induced edema is frequently seen in the emergency department.
Acquired angioedema. Acquired angioedema is probably the variant of angioedema that is most similar to HAE in terms of presentation and underlying pathology. Patients with acquired angioedema have a deficiency of C1-INH, but it is not genetic. Instead, the deficiency occurs as a result of either a lymphoproliferative disorder (type I) or an autoimmune disease (type II).
In type I acquired angioedema, complement C1 is activated by immune complexes that are formed by circulating anti-idiotypic antibodies against B-cell surface immunoglobulins. This activated C1 consumes circulating C1-INH, leading to symptoms. This disorder can occur secondary to an underlying B-cell lymphoproliferative disorder or possibly a rheumatic disease. (2,20,21)
In type II acquired angioedema, autoantibodies are produced against C1-INH, and they bind to the active site. (From a diagnostic viewpoint, it is important to note that the resulting cleavage fragment can be measured in plasma and can lead to apparently "normal" C1-INH assay results.)
In both types of acquired angioedema, C1-INH and C4 levels are low and Clq levels are reduced. In fact, a reduced C 1 q level distinguishes acquired angioedema from HAE, in which Clq levels are normal. The onset of acquired angioedema tends to occur around the fourth decade of life, which is later than that of HAE (second decade). Another difference is that patients with acquired angioedema have no family history of the disease.
Chronic idiopathic angioedema. In some patients, the recurrence of angioedema symptoms cannot be associated with any of the previously described variants. In these cases, the diagnosis is chronic idiopathic angioedema. In this type, serum complement levels and function are normal, symptoms may be persistent, and urticaria is often present. Laryngeal edema in these cases is rare.
The different pathologies of the various types of angioedema should drive specific approaches to prevention and treatment. For example, [H.sub.1] and [H.sub.2] antagonists, steroids, and epinephrine are the mainstays of the management of allergic angioedema, but they are of no benefit in HAE. Likewise, avoidance of allergens and triggering drugs is key to preventing both allergic and ACE-inhibitor-induced angioedema, but HAE triggers are often unknown. Therefore, a careful differential diagnosis and an understanding of the underlying processes are critical to effective management.
Because the course of HAE is unpredictable, patients and their families may live in constant fear of recurrences--and possibly even fatal outcomes. Therefore, the key goal of treatment is to minimize the impact of the disease on the patient's daily life. Routine prophylaxis to prevent recurrent symptoms, procedural prophylaxis to prevent attacks during planned surgical or dental procedures, and treatment of acute attacks should all be taken into consideration. (6)
Avoidance of triggers, when known, is important. In addition to avoiding some obvious triggers (e.g., trauma, mechanical pressure, repetitive activities, and stress), useful strategies may include minimizing the use of estrogen contraceptives and maintaining good oral health to avoid infection and lessen the need for dental procedures where possible. (22) The need for pharmacologic therapy, however, remains. Our increased understanding of the pathophysiologic basis of HAE has led to a number of developments in pharmacologic approaches to management, including C1-INH therapy, which has been used in Europe for more than 25 years but which has only recently been introduced in the United States.
Routine prophylaxis. Until recently, routine prophylaxis in the United States has been limited primarily to the use of attenuated (synthetic, 17-[alpha]-alkylated) androgens such as danazol, stanozolol, and oxandrolone, which have been shown to increase C1-INH and C4 concentrations, although the exact mode of action of these agents in HAE is not well understood. (23) The side effects of the androgens are milder than those of testosterone, but nevertheless these agents are either contraindicated or must be closely monitored in children, in pregnant or lactating women, and in men with prostate cancer. These side effects include weight gain, acne, vasomotor symptoms, menstrual irregularity, hypertension, atherosclerosis, virilization, hepatic neoplasms, and hair growth. Liver function must be monitored regularly to avoid hepatic necrosis, cholestasis, and abnormal lipoprotein metabolism. Patients should be maintained on the lowest possible effective dose; because these drugs have been shown to be effective at doses lower than those required to increase C1 and C4 levels, (24) changes in plasma levels of these proteins cannot be used as a guide to therapy. Possibly because effective alternatives have not been available in the United States, androgens have been the most widely used agents for many years.
Antifibrinolytic agents such as tranexamic acid and [epsilon]-aminocaproic acid have also been used for routine prophylaxis. However, their efficacy is limited, and they tend to be used in patients in whom androgens are contraindicated and in those who have not tolerated or responded to androgen treatment. (6) Known side effects of the antifibrinolytics include nausea, diarrhea, vertigo, muscle cramps, postural hypotension, and fatigue. They may also increase a patient's risk of thrombosis, tumor development, and teratogenicity. Their mechanism of action is unclear, and it is interesting that they exert no observable effects on plasma C1-INH levels. One possible explanation for their mechanism of action may be deactivation of plasminogen and a resulting decrease in the consumption of C1-INH, which constitutes a form of C1-INH sparing. (6)
Recently, a C1 inhibitor (Cinryze) was approved by the FDA for HAE prophylaxis. This agent increases the circulating amount of the deficient protein, and therefore it is effective for both type I and type II HAE. The C1-INH exerts its effects at several points in the complement, contact, and fibrinolytic systems (figure).
Craig et al recently reviewed points to consider when deciding which patients with HAE may benefit from routine prophylaxis]5 They concluded that those with frequent or severe attacks, a history of laryngeal attacks, significant anxiety, a significant impairment of activities of daily living, and poor quality of life should be considered for C1-INH prophylaxis, especially those patients who do not tolerate or respond to androgen therapy.
Procedural prophylaxis. Trauma, including that sustained during surgery or dental procedures, is a known trigger of HAE attacks, and even routine procedures can lead to fatalities due to asphyxiation. (1) Procedural prophylaxis is therefore indicated whenever such procedures are scheduled. (24,26) High-dose androgen therapy, such as oral danazol at 200 mg three times daily for 5 to 10 days prior to the procedure, may be used. Infusion of 2 U of fresh frozen plasma between 1 and 12 hours prior to a procedure has also been used, as has C1-INH at 500 to 1,000 U, depending on body weight, 1 hour prior to surgery, followed by a second dose at the time of surgery if needed. (27)
Acute treatment. In patients with laryngeal involvement who are at risk of asphyxiation, the first priority is stabilization of the airway by intubation, cricothyrotomy, or tracheotomy. Drug therapy with antihistamines, steroids, and epinephrine, which is usually effective in treating angioedema of other etiologies, is not likely to be effective in HAE. Until recently, the treatment of acute attacks in the United States was mainly limited to supportive therapy, such as fluid replacement and pain therapy for abdominal attacks. Fresh frozen plasma has been used to overcome C1-INH dysfunction. This is somewhat controversial, however, because it has the potential to exacerbate symptoms; fresh frozen plasma contains additional enzyme proteases and substrates that could theoretically worsen an attack. (28) Androgens and antifibrinolytics generally need 1 to 2 days to take effect, so they are not of significant benefit in acute treatment, (24,26) although danazol and related agents might shorten the duration of an attack if given early. (5)
Outside the United States, C1-INH therapy is recommended as a treatment of choice in acute attacks, particularly when there is a suspicion of airway involvement. (5,29) In the United States, the FDA recently approved another brand of C1-INH (Berinert) for the acute management of facial and abdominal attacks in adolescents and adults. Other emerging therapies, such as the bradykinin receptor antagonist icatibant and the kallikrein inhibitor ecallantide, have also been investigated for the acute treatment of HAE. The latter, which inhibits kallikrein and prevents subsequent bradykinin generation, was recently approved for this indication in the United States. A review of these emerging therapies, including early clinical data, was recently published by Frank. (30)
Care of the pregnant HAE patient. Pregnancy poses special treatment challenges for women with HAE, as there have been anecdotal reports that it leads to a worsening of HAE. (5) In general, attenuated androgens are contraindicated in pregnant women, but antifibrinolytics can be used with caution if necessary. C1-INH therapy can be used during pregnancy for prophylaxis. In a recent study by Baker et al, 6 pregnant women received Cinryze 1 or 2 times per week, and none experienced any HAE-related complications during pregnancy; all pregnancies culminated in normal healthy deliveries. (31)
As is the case with most drugs used during pregnancy, the risk benefit/ratio of HAE therapy must be considered. This includes consideration of the possibility that a patient will experience an attack of HAE during delivery itself. In the study by Baker et al, 1 other patient received Cinryze immediately prior to delivery and 2 days later, and she also experienced a normal delivery. (31) If a cesarean section becomes necessary, regional analgesia rather than intubation is preferable in order to avoid laryngeal trauma. (5) Finally, the risk of experiencing an HAE attack during the postpartum period should also be considered.
Ongoing developments in HAE management
The unpredictable nature of HAE, including the possibility that an attack will develop rapidly, means that a patient may not always be able to obtain immediate treatment at a medical facility. Therefore, it has been recommended that patients be offered C1-INH self-infusion programs to facilitate both prophylaxis and early treatment of acute events. (27) A number of studies provide support for this recommendation, (32-34) although it should be noted that only home-administered prophylaxis is an approved indication in the United States. Levi et al found that a group of patients who self-administered prophylactic C1-INH significantly reduced their mean attack rate from 4.0 to 0.3 per month. (32) Likewise, the same study found that patients who self-administered as needed experienced a significantly shorter time to resolution of acute attacks. (32) Bygum et al showed that patients who were trained to self-treat acute attacks according to a protocol based on international recommendations were able to resume a normal life without restrictions. (33) Longhurst et al reviewed a number of such initiatives and concluded that home therapy under the guidance of specialist HAE units can be a viable and effective option for patients and their families, especially when patients have a rapid onset of attacks or when access to a hospital is difficult. (34)
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(32.) Levi M, Choi G, Picavet C, Hack CE. Self-administration of C1inhibitor concentrate in patients with hereditary or acquired angioedema caused by C 1-inhibitor deficiency. J Allergy Clin Immunol 2006;117(4):904-8.
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Jack B. Anon, MD, FACS
From the Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh.
Correspondence: Jack B. Anon, MD, 3580 Peach St., Erie, PA 16508. Email: Jack@JackBAnon.com
Funding/support: Financial support for the preparation of this article was provided by ViroPharma Incorporated, and editorial support was provided by Innovative Strategic Communications, LLC.
Table 1. Features, symptoms, and laboratory findings in hereditary angioedema Type Features and symptoms Type I Features: An autosomal (80 to 85% dominant inherited disorder; a of HAE positive family history is present cases) in most patients (20 to 25% experience a spontaneous mutation); no sex or race pattern; triggers are often unknown Symptoms: Edema is present in the extremities, GI tract, and respiratory tract; abdominal swelling is accompanied by pain, vomiting, and diarrhea; life-threatening laryngeal edema is a major concern; urticaria is absent; symptoms appear in the second decade of life or earlier; symptom severity may increase postpuberty Type II Features: Same family history, (15 to 20% sex/race pattern, and triggers as of HAE noted for type I HAE cases) Symptoms: Same as noted for type I HAE Familial Features: Recurrent with normal angioedema, primarily in women; C1-INH etiology is unclear, but possibly (rare) involves a congenital mutation in factor XII expression in some families Symptoms: Indistinguishable from types I and II Laboratory findings Type C1-INH level C4 level C1q level * Type I Low Low Normal (80 to 85% of HAE cases) Type II Elevated or Low Normal (15 to 20% normal but of HAE dysfunctional cases) Familial Normal Normal Normal with normal C1-INH (rare) Type Management ([dagger]) Type I Drug therapy with an androgen (80 to 85% derivative, antifibrinolytic of HAE (e.g., tranexamic acid or cases) e-aminocaproic acid), or C1-INH concentrate; pain management (abdominal); fluid replacement; infusion of fresh frozen plasma; maintenance of an open airway (laryngeal) Type II Same as noted for type I HAE (15 to 20% of HAE cases) Familial C1-INH concentrate; efficacy with normal of androgen is unclear; C1-INH antifibrinolytics are ineffective (rare) * A normal Clq level distinguishes HAE from acquired angioedema, in which Clq levels are reduced. ([dagger]) These modalities are available (although not necessarily approved) in the United States for prophylaxis and/or acute treatment. Key: Cl -INH = Cl esterase inhibitor, HAE = hereditary angioedema. Table 2. Features, symptoms, and laboratory findings in other types of angioedema Type Features and symptoms Allergic Features: Most common form of angioedema; triggers (e.g., food, chemicals, drugs, bee stings, cold/ heat) provoke a histamine response Symptoms: Edema, most often affecting the face or throat; urticaria is likely present ACE- Features: Accounts for as many as inhibitor- 8% of angioedema cases; onset induced normally occurs within the first month of ACE inhibitor therapy, but may be delayed Symptoms: Edema at all sites; urticaria may occur, but it is not common Acquired Features: Linked to an underlying type I lymphoproliferative disorder (B-cell) or rheumatologic disorder; no family history or genetic link Symptoms: Similar to those of HAE; symptoms appear later in life, typically in the fourth decade Acquired Features: Autoantibodies produced type II against C1-INH (mainly IgG, but IgA and IgM have also been noted) bind to active site; no family history or genetic link Symptoms: Similar to those of HAE; symptoms appear later in life, typically in the fourth decade Chronic Features: Unclear etiology; no family idiopathic history; age of onset varies Symptoms: Persistent symptoms; edema at all sites, especially the face and lips; usually accompanied by urticaria Laboratory findings Type C1-INH level C4 level C1q level Allergic Normal Normal Normal ACE- Normal Normal Normal inhibitor- induced Acquired Low Low Reduced type I ([dagger]) Acquired Low Low Reduced' type II Chronic Normal Normal Normal idiopathic Type Management * Allergic Trigger avoidance; drug therapy with an antihistamine or steroid; epinephrine for emergencies ACE- Trigger avoidance; ACE inhibitor- inhibitors are induced contraindicated Acquired Treat the root cause; type I prophylaxis with an androgen, antifibrinolytic, or C1-INH Acquired Androgen, antifibrinolytic, type II or C1-INH Chronic Antihistamine, steroid, or idiopathic epinephrine * These modalities are available (although not necessarily approved) in the United States for prophylaxis and/or acute treatment. ([dagger]) A reduced Clq level distinguishes acquired angioedema from HAE, in which Clq levels are normal. Key. CI-INH = Cl esterase inhibitor; ACE = angiotensin-converting enzyme; HAE = hereditary angioedema.
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|Title Annotation:||ORIGINAL ARTICLE|
|Author:||Anon, Jack B.|
|Publication:||Ear, Nose and Throat Journal|
|Date:||Jan 1, 2011|
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