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Hereditary Angioedema
A Broad Review for Clinicians
Ugochukwu C. Nzeako, MD, MPH;
Evangelo Frigas, MD;
William J. Tremaine, MD
Arch Intern Med. 2001;161:2417-2429.
ABSTRACT
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Hereditary angioedema (HAE) is an autosomal dominant disease that afflicts
1 in 10 000 to 1 in 150 000 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 triggers. 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.
Corticosteroids, 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.
INTRODUCTION
Angioedema is an intense, usually disfiguring, temporary swelling of
a localized body area. It most commonly occurs as part of an allergic response
to exogenous substances and conditions. Such substances may be dietary in
origin, eg, shellfish and other seafood, or may be environmental, as is the
case with temperature-related angioedema. The sporadic exogenous phenomena
that result in angioedema may be prevalent in up to 10% of the population.1 Use of some drugs prescribed for common ailments,
such as angiotensin-converting enzyme (ACE) inhibitors for hypertension, renal
disease, and cardiac disease, can also induce an adverse reaction in apparently
healthy individuals and result in angioedema.
In a few individuals, angioedema occurs because of an intrinsic defect
that abolishes one of the body's several safeguards against such occurrences.
This defect allows a cascade of events that culminates in symptoms. This form
of angioedema occurs as a result of either an inherited defect in C1 esterase
inhibitor (C1-INH) activity or an acquired deficiency of C1-INH. The inherited
form of the disease, known as hereditary angioedema (HAE), is rare, although
it is more common than acquired angioedema (AAE).
Traditionally, 2 types of HAE have been described. Type 1 HAE, which
is estimated to occur in 80% to 85% of patients, is caused by the decreased
production of C1-INH, resulting in subnormal blood and tissue inhibitor activity.
In type 2 HAE, which occurs in the remaining 15% to 20% of patients, normal
or elevated quantities of functionally impaired C1-INH are produced. Recently,
a third type of HAE in which C1-INH levels and function are normal has been
described, so far only in women.2
All types of HAE have identical symptoms characterized by edema of 1
or several organ systems. The skin, gastrointestinal tract, and respiratory
tract are most commonly involved. Cutaneous angioedema involves deeper layers
such as the inner dermis and subcutaneous tissue, unlike urticaria, which
is common in angioedema from other causes and involves the epidermis and upper
dermis. The absence of pruritus, and the often-present associated visceral
symptoms, makes angioedema distinguishable from urticaria.
HISTORY OF HAE
J. L. Milton first described angioedema in 1876.3
The subsequent article by Quincke in 18824
was the first to assign the name angioneurotic edema
to the disease. A review of the literature suggests that the word neurotic was used as part of the name in an attempt to describe the
observed effect of mental stress on exacerbations of this disease. In 1888,
William Osler5 published the first article
describing a hereditary form of angioneurotic edema; however, discovery of
the biochemical basis for the disease did not occur until several decades
later. A seminal study published in 1963 by Donaldson and Evans6
first described the biochemical abnormality responsible for HAE: the absence
of C1-INH in patients with the disease. Since that study, the body of knowledge
regarding the clinical manifestations, spectrum, pathophysiology, and genetic
basis of the various forms of angioedema has broadened considerably.
CLINICAL PRESENTATION
Symptoms of HAE are usually mild or nonexistent during early childhood,
typically first manifesting during the second decade of life. However, a few
patients present during their first decade. Although some attacks lack an
identifiable trigger, most are associated with trauma, medical procedures,
emotional stress, menstruation, oral contraceptive use, infections, or the
use of medications such as ACE inhibitors.7
Typically, acute HAE manifests as marked diffuse edema involving all
skin layers and layers of the walls of hollow visceral organs and solid organs.
Most visceral organs are susceptible and can be affected singly or in any
combination. Typical attacks of angioedema last approximately 2 to 5 days
before resolving spontaneously. Skin edema is nonpitting, with ill-defined
margins, and most commonly affects areas of the face, extremities, and genitals.
Facial areas typically involved are the lips, eyelids, and tongue. More often,
genital edema occurs as a result of trauma during intercourse, parturition,
and even horseback riding.8-9
During acute attacks, patients may develop a rash similar to that seen in
urticaria. Unlike urticaria, however, the skin lesions associated with HAE
are erythematous but not warm, painful, or pruritic.
When edema occurs in the walls of the respiratory and gastrointestinal
tract systems, the most ominous and distressing symptoms of HAE occur. Thus,
laryngeal, nasal, and sinus edema may lead to respiratory tract compromise
and death from suffocation. In such circumstances, tracheostomy can be lifesaving
because the edema associated with acute episodes typically occurs at, or above,
the larynx. If undiagnosed, mortality from HAE can be as high as 30% to 40%,
mostly due to upper airway obstruction.10-11
Even in those with known HAE, unnecessary delay in seeking or administering
appropriate medical treatment has often resulted in asphyxiation. Asphyxiation
can occur at any age and has been documented in individuals as young as 4
weeks and as old as 78 years. Patients with no previous history of upper airway
involvement during acute HAE exacerbations still run a risk of asphyxiating.
In a recent study,11 5 of 6 individuals who
asphyxiated during acute HAE had never experienced upper airway involvement
during previous attacks. The time from symptom onset to asphyxiation also
varies, ranging from as little as 20 minutes to as long as 14 hours. Transient
pleural effusions, sometimes with cough and mild pleuritic chest pain, can
also occur.9
Gastrointestinal tract symptoms of HAE, caused by visceral edema, result
in varying degrees of intestinal obstruction. Thus, typical symptoms of gastrointestinal
tract involvement are anorexia, vomiting, and crampy abdominal pain that can
be severe. The abdomen is typically tender to palpation, usually without guarding.
Ascites, as a result of fluid extravasation into the peritoneal cavity, occurs
occasionally. In one study,12 ascites from
acute HAE was significant enough to cause hypovolemic shock; however, the
concomitant vasodilation known to occur during acute exacerbations probably
played an additive role. Diarrhea can also occur, particularly as the acute
episode resolves. Gastrointestinal tract HAE presenting as severe cramps,
nausea, and vomiting, and unaccompanied by cutaneous symptoms, can be mistaken
for an acute abdomen. This occasionally leads to unnecessary surgical abdominal
exploration and the excision of otherwise normal gallbladders and appendixes.
In fact, without a high index of suspicion, gastrointestinal tract HAE may
be undiagnosed for decades despite patients presenting repeatedly to the emergency
department with these complaints. In such circumstances, symptoms have occasionally
been attributed to psychosomatization, with patients inappropriately referred
for psychiatric assessment. Attacks of gastrointestinal tract angioedema generally
subside within 12 to 24 hours, whereas cutaneous angioedema persists for several
days.13
Two case reports14-15 describe
migrainelike and transient ischemic attack symptoms during acute HAE. Others9, 16-17 have reported seizures
and hemiparesis. These symptoms are thought to be caused by local cerebral
edema and consequent cerebral hypoperfusion, caused by the acute HAE episode.
Fever and leukocytosis are unusual in acute HAE, and their presence
during an attack in a person known to have HAE should raise suspicion that
another process, such as infection or intra-abdominal catastrophe, may be
the inciting event for the acute exacerbation.
Pregnancy has been associated with a decrease in serum C1-INH levels,
even in women with no genetic evidence of HAE,18-19
but pregnancy does not increase the risk of attacks. In fact, pregnancy has
often been associated with decreased attack frequency.9
These counterintuitive observations may be explained by the finding that the
total amount of circulating C1-INH actually increases during pregnancy; however,
a decrease in the measurable level occurs as a consequence of the significant
physiologic increase in plasma volume that occurs concomitantly.18
A study20 of one kindred with HAE suggested
that significantly more pregnant patients with HAE (60%) experienced premature
labor than did pregnant family members without HAE; however, a causal relationship
has not been established. Levels of C1-INH are also decreased further in some
pregnant women with preeclampsia and eclampsia, and the role of low C1-INH
levels in these conditions is currently being investigated.19, 21
Increased attack frequency has been reported22
in association with menstruation and oral contraceptive use.
EPIDEMIOLOGIC CHARACTERISTICS
Data on the epidemiologic characteristics of HAE are sparse. Estimates
of its incidence worldwide vary, from 1 in 10 00023
to 1 in 150 000 persons.24 Types 1 and
2 HAE have been reported in all races, and no sex predominance has been found.
However, a recently described third type of inherited angioedema has been
found only in women.2 Seventy-five percent
of patients with HAE have cutaneous angioedema of an extremity as the first
presenting sign of the disease. Recurrent abdominal pain and upper airway
and facial edema occurred in 52% and 36%, respectively, of patients in one
series.9 In 39% of these cases, patients could
attribute their first episode to an identifiable traumatic event.9
Most patients with symptomatic untreated HAE experience at least 1 acute
exacerbation per month, and because each attack typically lasts a few days
before spontaneously subsiding, it is estimated that individual patients can
be debilitated by their symptoms for 20 to 100 days per year.3
PATHOPHYSIOLOGIC AND IMMUNOLOGIC FEATURES OF TYPES 1 AND 2 HAE
C1 esterase inhibitor, an  2-globulin of approximately
105 kd, belongs to the serine protease inhibitor family that includes 1-antitrypsin and antithrombin. It is encoded on chromosome 11 and is
synthesized mainly by hepatocytes, although peripheral blood monocytes can
also synthesize significant quantities. Skin fibroblasts have also been shown
to synthesize this protein, but their contribution to the body's pool of C1-INH
in physiologic circumstances in vivo is unknown.25
Cytokines, particularly interferon  , can stimulate synthesis of C1-INH
in these cells in vitro.25 Interleukin 6, an
important proinflammatory cytokine, increases the release of C1-INH from HepG2
hepatoma cells in vitro. This action was potentiated by the presence of another
proinflammatory cytokine, interleukin 1, which by itself has no effect on
C1-INH synthesis or secretion.26-27
Thus, C1-INH synthesis in vivo can be regulated, at least in part, by these
cytokines.
The major functions of C1-INH within the human body include the prevention
of C1 complement autoactivation; inactivation of coagulation factors XIIa,
XIIf, and XIa; and direct inhibition of activated kallikrein.22
Its role in factor XIa inactivation is a minor one, however, with 1-antitrypsin being primarily responsible for inactivating this factor.
In general, the direct inhibitory effect of C1-INH is achieved by the formation
of irreversible covalent bonds with these substrates, forming inactive C1-INH
complexes.
To facilitate a clear understanding of the role of C1-INH in the inactivation
of its various substrates, brief reviews of the classical pathway of complement
activation and of the contact (kallikrein/kinin) system are necessary.
The Complement Cascade
Nine complement components (C1-C9), and 2 pathways of complement activation
(classical and alternative) have been described. C1 complement is a trimolecular
heteropentameric complex composed of 1 C1q, 2 C1r, and 2 C1s components,28 all of which are linked through calcium molecules.
In the classical pathway, interaction between the immunoglobulin Fab fragment
and its target antigen results in complement activation, initiated through
the binding of C1q to the constant heavy regions of the immunoglobulin Fc
fragment. C1r is subsequently recruited, and complexes first with bound C1q
and then with C1s. This binding activates C1s, which acquires esterase activity
and cleaves C4, thereby initiating a cascade of events that generates a complex
of complement fragments termed the membrane attack complex. This complex is responsible for the cell membrane damage that results
in lysis of cells targeted by the specific immunoglobulins. During this cascade,
C3a, C4a, and C5a are generated, cause increased capillary permeability, and
contribute to edema and swelling of skin and organs that may be seen with
massive complement activation, as occurs during an attack of HAE (Figure 1).
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Figure 1. C1 esterase inhibitor prevents
autoactivation of complement component C1, thus keeping the classic complement
pathway quiescent. MAC indicates membrane attack complex.
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In humans, it is believed that circulating C1 can undergo autoactivation
and that it does so in increasing quantities when C1-INH is insufficient or
absent. A discussion of evidence for such autoactivation is beyond the scope
of this review; however, several detailed articles have been written on the
subject.22, 25, 29-32
C1 esterase inhibitor prevents this autoactivation of C1 complement by causing
dissociation of the C1q subunit and by forming an inactive C1r2-C1s2-(C1-INH)2 complex.22, 25
This complex is unable to cleave and activate complement components C4 and
C2, the usual substrates of activated C1, thus keeping the classical pathway
quiescent (Figure 1).
The Contact (Kallikrein-Kinin) System
Results of quantitative kinetic experiments32-33
suggest that C1-INH activity is responsible for inactivating approximately
90% of factor XIIa and its metabolite factor XIIf (Figure 2). Approximately 42% of plasma kallikrein is inactivated
by C1-INH activity,22 approximately 50% is
inactivated by 2-macroglobulin, and the remaining 8% is
inactivated by other minor inhibitors.
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Figure 2. C1 esterase inhibitor inactivates
factors XIIa and XIIf, plasmin, and kallikrein, thus preventing bradykinin
production.
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Inactive precursor components of the contact system include high-molecular-weight
kininogen and prekallikrein. Factor XII is technically not a component of
the contact system, but it plays a significant role in its activation. It
is hypothesized that in healthy individuals, small quantities of factor XII
are constantly autoactivated to factor XIIa, possibly by a multitude of contacts
between circulating factor XII and negatively charged initiator surfaces within
the body.33 Factor XIIa is cleaved during its
metabolism to another active molecule, termed factor XIIf. Unopposed activation
of even small quantities of factor XII to factors XIIa and XIIf result in
an increasing positive feedback loop, with factor XIIa cleaving and activating
further molecules of factor XII. Because C1-INH is the major inhibitor of
factor XIIa, a decrease in its level and activity allows generation of significantly
increased quantities of factors XIIa and XIIf. Trauma, such as that seen during
surgery and dental manipulation, also exposes large areas of negatively charged
tissue and endothelial surfaces, which also results in activation of circulating
factor XII.9
Factor XIIa also cleaves prekallikrein to the active enzyme kallikrein.
Kallikrein in turn cleaves high-molecular-weight plasma kininogens, resulting
in excessive release of various kinins, especially bradykinin and kallidin.
Subnormal C1-INH activity also results in loss of its direct inhibitory effect
on kallikrein activity, thus further promoting bradykinin generation. The
large quantity of bradykinin released during acute attacks of HAE or AAE is
thought to be responsible for most symptoms by directly causing increased
vascular permeability (edema, swelling, and ascites), vasodilation (congestion,
erythema, and hypotension), and contraction of nonvascular smooth muscle (cramps,
spasms, and pain). By increasing capillary permeability, C3a, C4a, and C5a
may also contribute to local edema of skin and visceral organs, ascites, and
intravascular volume depletion.
Kallikrein also cleaves plasminogen to the active enzyme plasmin. In
addition to its better-known role of fibrin breakdown, plasmin also activates
factor XII, cleaves prekallikrein to produce even more kallikrein, and activates
C1 (Figure 3). At the tissue level,
plasmin activity may play a role in acute exacerbations of HAE; however, its
role in plasma is probably short-lived because of its rapid inactivation by 2-antiplasmin and 2-macroglobulin, its major inhibitors
in plasma.22
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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.
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Factor XIIf activates complement component C1, thus initiating the classic
pathway. Together with the constant autoactivation of complement component
C1 that occurs unchecked when C1-INH activity is subnormal, activation and
consumption of C4 and C2 occur during acute HAE attacks, resulting in profoundly
decreased serum levels. Levels of C4, and sometimes C2, are typically less
than normal during symptomatic quiescence, showing ongoing low-grade consumption
between attacks; however, these levels may return to normal in some patients
between attacks.9, 24, 34
Recent studies35-38
have shown that bradykinin, not a C2 kininlike peptide, is responsible for
most of the symptoms of acute HAE (Figure
2). Supporting data include the following: (1) large amounts of
activated kallikrein are present in induced blister fluids of patients with
HAE39; (2) levels of prekallikrein and high-molecular-weight
kininogen are decreased during acute HAE exacerbations40;
(3) plasma bradykinin levels increase significantly in persons with acute
HAE and in those experiencing ACE inhibitor therapy– related angioedema35; and (4) venous blood bradykinin levels were significantly
higher in samples taken from the affected vs unaffected arm of patients with
localized HAE exacerbation.36
Typical HAE attacks usually subside spontaneously after 2 to 5 days.
However, the risk of death from a vicious cycle of bradykinin and complement
fragment production exists during every acute episode until appropriate therapy
is administered to raise serum levels of active C1-INH or until spontaneous
remission occurs. Spontaneous remission may occur because the rapid consumption
of various substrates during the acute attack rapidly outstrips the body's
ability to manufacture them.
In patients with angioedema from causes other than heredity, urticaria
is a frequent accompanying symptom. Urticaria seems to be primarily a histamine-mediated
event, whereas angioedema seems to be mediated primarily by bradykinin. This
explains why patients with acute HAE typically have no urticaria. However,
urinary histamine excretion is increased in 18% of patients with acute HAE,
suggesting increased systemic histamine release during this process.41-42 Complement fragments C3a, C4a, and
C5a, and small fragments of C2 and bradykinin, all of which are produced in
large quantities during acute HAE attacks, can cause mast cell degranulation.23 Although total levels of complement component C3
usually remain normal during attacks, its turnover is increased (Figure 3).43
ASSOCIATED DISEASES
Patients with HAE have an increased incidence of autoimmune diseases.
An estimated 2% of patients also have systemic lupus erythematosus.44-45 This association has a strong female
preponderance and, although patients seem to have less severe manifestations
of systemic lupus erythematosus overall, skin lesions are prominent.46 In one study,45 approximately
12% of patients with HAE had an associated autoimmune disorder. This high
proportion mainly comprises arthritides, thyroiditis, glomerulonephritis,
and inflammatory bowel disease, all of which have been reported to occur at
a greater incidence in these patients. Rarely, Sjögren syndrome, drug-induced
lupus, pernicious anemia, scleroderma, and autoimmune aortitis have also been
associated with the disease.9, 20, 45
VARIANT ("TYPE 3") HAE
A recent German study2 described recurrent
angioedema in 10 female probands and 26 of their female relatives in the setting
of normal C1-INH level and function. These patients all manifested symptoms
indistinguishable from types 1 and 2 HAE, such as recurring skin lesions,
abdominal cramps, and laryngeal edema. Eighteen (50%) of these women had experienced
at least 1 episode of laryngeal edema, whereas 15 had experienced multiple
episodes (range, 2-200 episodes). Three of the women died of asphyxiation.
Age at onset varied widely, but most patients developed initial symptoms in
their second decade of life, as in the better-known types 1 and 2 HAE. Twenty-two
(61%) of patients developed initial symptoms between ages 10 and 23 years,
and 7 (19%) developed symptoms between 1 and 10 years of age. Like HAE, acute
exacerbations of this variant have been linked to oral contraceptive use (10
patients [28%]).
In patients with this variant, C1-INH level and function and C4 levels
are normal during active angioedema and when asymptomatic. This variant most
likely represents a congenital deficiency of enzymes such as ACE, carboxypeptidase
N, and 2-macroglobulin or a phenotypic decrease in the function
of these enzymes. Another possibility is that these individuals produce an
as yet unknown substance that is not regulated by C1-INH and that is capable
of cleaving large quantities of high-molecular-weight kininogen to produce
bradykinin. Because C1-INH exerts inhibitory actions on kallikrein and factors
XIIa and XIIf and because C1-INH levels are normal in these patients, the
physiological defect responsible for angioedema in these patients is probably
downstream of kallikrein (Figure 3).
The absence of detectable abnormalities in C1-INH level or function,
or in C4 levels, even during acute exacerbations of angioedema, makes it likely
that this entity will receive its own unique nomenclature. So far, the defect
has been found only in women, suggesting an X-linked–dominant pattern
of inheritance, and X-linked angioedema may be an
appropriate name.
GENETICS OF HAE
The gene encoding C1-INH has been cloned. It is located on chromosome
11q11-q13.1, possesses 7 exons and approximately 7 introns, and contains multiple
Alu repeat sequences.47-48 Hereditary
angioedema has an autosomal dominant pattern of inheritance, although it is
estimated that 20% to 25% of cases are the result of spontaneous mutations
in persons with no family history of the disease.49-50
All patients described in the literature have been heterozygotes. Thus, by
mendelian inheritance, affected individuals inherit one normal gene and one
abnormal gene, and a child of an affected patient has a 50% chance of acquiring
the abnormal allele. The abnormal gene is either nonfunctional and thus is
not transcribed (type 1 HAE) or codes for the synthesis of normal quantities
of an abnormal C1-INH protein (type 2 HAE).
Type 1 HAE is caused by a variety of mutations with deletions or insertions
of single or multiple nucleotides in the C1INH gene,
whereas type 2 HAE results from the synthesis of a dysfunctional C1-INH protein,
usually caused by point mutations in the areas coding for the "reactive center"
or "hinge region" of the C1-INH protein.51-52
The reactive center of C1-INH is the site that binds and cleaves target molecules.
It is located at the Arg444-Thr445 site of the C1-INH molecule and requires
an intact peptide bond between these 2 amino acids for proper function.25 Some mutations in the C1INH
gene result in substitutions at Arg444 of the C1-INH protein, and such mutations
have been estimated to account for up to 70% of those with type 2 HAE.51-53 Such mutations result
in an amino acid change, from arginine to others such as cysteine or histidine
at position 444. Other mutations within the reactive loop, but distant from
the reactive center, have been described. One such mutation in a patient with
type 2 HAE resulted in the substitution of threonine for alanine at position
436 of the C1-INH molecule.54 To date, more
than 100 different C1-INH mutations have been identified
in patients with HAE, and their varied effects on C1-INH protein synthesis
and function may explain the observed clinical differences in disease severity
in affected individuals.51, 55
Homozygous C1-INH deficiency has not been described.
The exact chromosomal abnormality responsible for the recently described
inherited variant, in which recurrent angioedema occurs in females with normal
C1-INH and C4 levels and function, is unknown.2
No affected males were identified, and these women came from 10 different
families, with 2 to 7 members affected in each family. Findings from pedigree
studies2 of these families suggest an X-linked–dominant
pattern of transmission; on occasion, the disease would skip one generation
of females and affect the subsequent generation. Thus, the asymptomatic daughter
of an affected woman may give birth to female offspring who ultimately manifest
the disease.
Phenotypically, type 1 HAE manifests as subnormal C1-INH levels, as
low as 5% to 30% of normal, with resultant decreased activity.22
Type 2 HAE results in synthesis of normal and mutant protein. The C1-INH functional
activity of the mutant protein is impaired despite the presence of normal
or supranormal serum levels. Because patients with type 2 HAE possess one
normal and one abnormal allele, theoretically their pool of C1-INH should
consist of 50% normal protein and 50% mutant protein. However, it has been
found that levels of normal C1-INH protein in these patients are typically
far below 50% (range, 5%-30%), despite evidence that synthesis of this normal
protein in these patients occurs at approximately half the rate seen in individuals
without HAE.56 Such low levels are thought
to occur because the single normal allele cannot increase synthesis of normal
C1-INH to a rate necessary to keep pace with its consumption.22
The finding that the fractional catabolic rate of normal C1-INH is increased
by approximately 29% in patients with HAE lends support to this hypothesis.56-57
ACQUIRED ANGIOEDEMA
Acute attacks of angioedema can also occur because of the acquired form
of the disease. Acquired angioedema results from increased destruction or
metabolism of C1-INH. Patients with AAE do not have the genetic mutations
of HAE. Typically, the first exace |
