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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 exacerbations of HAE occur during the second
decade of life or earlier, whereas AAE usually becomes symptomatic during
or after the fourth decade.
Two types of AAE have been described. Type 1 AAE typically occurs in
patients with rheumatologic disorders and B-cell lymphoproliferative diseases,
including leukemia (chronic lymphocytic leukemia), lymphosarcoma, multiple
myeloma, macroglobulinemia, and essential cryoglobulinemia.22
Rarely, it has been reported in association with carcinomas (rectal, gastric,
and breast), lupus anticoagulant, Churg-Strauss vasculitis, erythrocyte sensitization,
livedo reticularis, infections (human immunodeficiency virus, hepatitis C
virus, hepatitis B virus, Echinococcus granulosus,
and Helicobacter pylori), and, in one instance, T-cell
lymphoma.13, 58-60
These patients have circulating anti-idiotypic antibodies against specific
immunoglobulins expressed on the surface of B cells. Thus, immune complexes
are continually being formed between anti-idiotypic antibodies and surface
immunoglobulins on the cell surface, and these complexes in turn are thought
to continuously activate complement component C1. C1 esterase inhibitor is
consumed as it inactivates these large quantities of C1, and, ultimately,
because C1-INH synthesis cannot keep up with its consumption, levels decline
below normal, setting the stage for acute attacks of angioedema.
In type 2 AAE, autoantibodies (typically IgG and sometimes IgA or IgM)
directed against the C1-INH molecule are produced and released into the patient's
circulation. These bind the active site of the C1-INH molecule, leading to
its inactivation.35, 61-62
After inactivation of the normal 105-kd C1-INH molecule through binding with
autoantibody, an inactive 96-kd C1-INH fragment is cleaved from the bound
C1-INH molecule and circulates in the patient's blood, where it can be measured.
This fragment can lead to the finding of "normal" C1-INH levels on some laboratory
assays, in the setting of markedly attenuated C1-INH activity. Once the 96-kd
fragment is cleaved, the autoantibody dissociates from the C1-INH remnant
to which it was bound and proceeds to bind with a fresh 105-kd C1-INH molecule.
Thus, low levels of autoantibody can result in inactivation of large quantities
of C1-INH.13 Analysis of autoantibodies to
C1-INH has shown that patients produce antibodies that recognize different
epitopes within the C1-INH molecule.
As described earlier in the section "The Complement Cascade," small
amounts of C1 complement autoactivate on a continuous basis in humans. In
unaffected individuals, normal levels of C1-INH inactivate these molecules
and prevent full activation of the classic complement pathway. However, in
patients with AAE, in whom C1-INH levels are already significantly decreased
via consumption or inactivation, C1-INH is further consumed as it performs
its housekeeping functions, including inactivation of autoactivated C1. In
fact, the fractional catabolic rate of C1-INH in patients with AAE is more
than twice that seen in unaffected individuals and approximately 1
times that in individuals with HAE.57
Patients with AAE have significantly decreased serum levels of classic
complement components, particularly C1q, C4, and C2. In particular, decreased
serum C1q levels help distinguish AAE from HAE, in which C1q levels are usually
normal. The decreased C1q levels seen in AAE but not in HAE reflect the central
role of C1 autoactivation and consumption in driving the symptoms of AAE via
C1-INH depletion and consequent contact system autoactivation.
A 12% prevalence of autoantibodies to C1-INH has also been reported
in patients with liver cirrhosis.63 Although
these patients had significantly lower quantitative C1-INH levels than those
without autoantibodies, they did not develop acute angioedema.
ACE INHIBITOR THERAPY-INDUCED ANGIOEDEMA
A variety of commonly prescribed medications have been associated with
the occurrence of angioedema in healthy individuals, including antibiotics,
narcotic and nonsteroidal analgesics, angiotensin II inhibitors (losartan
potassium), and ACE inhibitors. Allergic phenomena seem to play a major role
in all except ACE inhibitor therapy–related angioedema. Although allergic
and immunologic mechanisms, such as the "hapten hypothesis" in the case of
captopril, have been proposed to explain ACE inhibitor therapy–related
angioedema, they do not explain the constellation of manifestations and laboratory
findings seen in this condition. Urticaria, which sometimes occurs concomitantly
in ACE inhibitor therapy–related angioedema, is more aptly explained
by the hapten hypothesis than is angioedema.
Most of the structurally diverse ACE inhibitors on the market have been
reported to cause angioedema (Table 1).1 Angiotensin-converting enzyme has 2 main substrates
in the human body, angiotensin I and bradykinin, which it cleaves into smaller
molecules. In the case of bradykinin, this cleavage inactivates the molecule.73 Because bradykinin excess has been implicated at
the tissue level in HAE, ACE inhibitors may induce angioedema in susceptible
individuals by causing bradykinin accumulation with resultant vasodilation,
capillary leakage, and edema.
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Table 1. Cases of Gastrointestinal Tract Angioedema Related to Angiotensin-Converting
Enzyme (ACE) Inhibitor Therapy in the English-Language Literature*
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Angiotensin-converting enzyme, also called kininase II, is widely distributed
in the human body. It is still unclear why only a few individuals develop
angioedema from ACE inhibitor therapy, whereas most do not. Patients who develop
angioedema while taking an ACE inhibitor may be those with a congenital or
acquired impairment in carboxypeptidase N activity (also called kininase I,
which degrades bradykinin), which would lead to significant accumulation of
bradykinin once ACE activity is blocked.74
Use of ACE inhibitors has been associated with angioedema in approximately
0.1% to 0.5% of cases.1, 75-76
No sex predominance has been noted in patients without gastrointestinal tract
involvement. In contrast, all patients described in the literature of ACE
inhibitor therapy–associated angioedema in whom gastrointestinal tract
involvement has occurred have been women.64
This has led to speculation about a possible sex-linked susceptibility to
gastrointestinal tract involvement.
Although the onset of angioedema typically occurs during the first week
of therapy with these agents, symptoms have occurred as long as 2 to 3 years
after the first medication use.1, 65
Symptoms resolve within 24 to 48 hours of discontinuing the drug therapy and
typically recur on rechallenge with the same, or another, ACE inhibitor. Upper
airway obstruction rarely occurs in patients with angioedema secondary to
ACE inhibitor use. One study77 has proposed
that previous upper airway trauma, instrumentation, or manipulation may represent
a risk factor for developing such upper airway obstruction secondary to ACE
inhibitor therapy–related angioedema.
Findings on physical examination and radiologic testing are similar
to those seen in HAE. However, unlike in HAE, a mild to moderate leukocytosis
has been noted in some studies64, 66-68
of ACE inhibitor therapy–related angioedema.
Angioedema resulting from ACE inhibitor use can be distinguished from
HAE and AAE only by history, C1-INH levels, and complement assays. Most patients
who develop ACE inhibitor use–related angioedema have normal C1-INH
levels and function. However, ACE inhibitors trigger attacks when taken by
individuals with HAE.
Treatment consists of discontinuing use of the ACE inhibitor. Antihistamines,
anticholinergics, and corticosteroids are useful when urticaria occurs with
angioedema but are ineffective if use of the ACE inhibitor is continued.67 Subcutaneous (1:1000 mixture) and nebulized epinephrine
should be administered in cases in which the airway is threatened, as outlined
in the "Management" section.
CHRONIC IDIOPATHIC ANGIOEDEMA
In some instances, chronic recurrent angioedema cannot be attributed
to HAE, AAE, or any of the known drug-induced and physical causes. Patients
with such symptoms have been deemed to have chronic idiopathic angioedema
(CIA). This is an important differential diagnosis for such patients, because
its management differs from that for HAE. In most instances, chronic urticaria
is also present. The clinical presentations of CIA and HAE are similar, but
pruritus typically accompanies CIA and laryngeal edema is rare.
Antihistamines and, in severe or refractory cases, corticosteroids are
the mainstay of therapy. Histamine1 receptor antagonists provide
symptomatic relief in most instances, but the addition of histamine2 receptor antagonists seems to provide additional relief in a few patients.
If use of antihistamines does not provide symptomatic control, corticosteroids
may be administered. The details of management of CIA are well documented23, 78 but are beyond the scope of this
review.
Patients with CIA, particularly those with frequent and persistent episodes,
should undergo annual general medical evaluation to investigate for any underlying
occult disease.
DIAGNOSIS
Hereditary angioedema is transmitted in an autosomal dominant pattern,
and the parents, siblings, and offspring of patients with HAE should be tested
and receive genetic counseling. Some individuals with biochemical findings
consistent with HAE never experience an acute exacerbation of the disease.79 We80 described a patient
with HAE whose 53-year-old father was asymptomatic despite having decreased
C1-INH function (37%) in the setting of normal serum levels. Other patients
do not manifest symptoms of the disease until as old as 70 years.23 In 20% to 25% of patients with HAE, there is no family
history of the disease.16, 49-50,79
Therefore, a positive family history of HAE is not a prerequisite for consideration
of HAE in the differential diagnosis when typical symptoms are present.
In the patient with suspected HAE who is currently asymptomatic, serum
C1-INH activity should be measured. If this is subnormal, then quantitation
of C1-INH and C1q levels will help distinguish between HAE and AAE.3 Patients with HAE will have markedly decreased C1-INH
activity and normal C1q levels, with decreased (type 1), normal, or supranormal
(type 2) levels of C1-INH. Those with AAE will also show a marked decrease
in C1-INH activity; however, C1q levels are concomitantly decreased below
normal (Table 2).
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Table 2. Classification and Distinguishing Features of Hereditary and
Acquired Angioedema*
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During an acute presentation of symptoms consistent with HAE, C4 and
C2 levels are markedly decreased, sometimes to undetectable levels, and therefore
are useful confirmatory tests. Complement is chronically consumed in patients
with HAE even between exacerbations, albeit at a much slower rate than that
seen in acute exacerbations. The C4 level is persistently low in most, but
not all, patients, whereas the C2 level may remain decreased in a smaller
proportion of patients. In a few patients, C4 and C2 levels normalize in the
absence of symptoms.9, 24, 34
There is no correlation between the magnitude of decrease in C1-INH level
or activity and the severity or frequency of acute HAE attacks. In newly symptomatic
middle-aged or older patients with biochemical findings of HAE, C1q quantitation
should be performed to rule out AAE.
Heparinization, such as that attained during management of cardiac ischemia
or cardiac bypass surgery, has been associated with spuriously elevated C1-INH
activity.81 Thus, if C1-INH function is normal
in a heparinized patient when the index of suspicion for HAE is high, the
C1-INH functional assay should be repeated a week after the discontinuation
of heparin therapy.
Diagnosis of the recently described HAE variant in the setting of recurrent
angioedema requires a detailed personal and family history, pedigree analysis,
and biochemical evidence of normal C4, C1q, and C1-INH levels and function
during symptomatic and asymptomatic periods. The personal history must rule
out all other causes of isolated angioedema, including drugs, food allergens,
and environmental and topical allergens.
Patients with acute gastrointestinal tract HAE have been inadvertently
subjected to endoscopy when the diagnosis is unknown. Any instrumentation
of the oropharynx is relatively contraindicated when acute HAE is considered
the leading differential diagnosis in a patient with acute abdominal pain
because of the risk of inducing life-threatening laryngeal edema. If there
are compelling reasons why upper endoscopy should be done in this circumstance,
appropriate prophylaxis, as described in the "Management" section, is necessary.
Nonetheless, the endoscopic appearance of gastrointestinal tract HAE has been
described, with findings of diffuse mucosal edema and erythema, with bulging
masses of gastric mucosa resembling a submucosal tumor.82
All the gastric lesions had resolved at second endoscopy 8 weeks later. Similar
lesions noted along the small intestine on imaging studies are thought to
be responsible for the radiographic appearance and obstructive symptoms seen
during acute attacks.
Stomach mucosal biopsy samples taken during attacks of HAE show moderate
nonspecific inflammatory cell infiltration and edema of the lamina propria.82-83 Plain radiographs and computed tomographic
scans of the abdomen typically show varying degrees of ileus (sometimes with
air-fluid levels) and small-bowel thickening, respectively. "Thumbprinting"
and a stacked coin appearance, also signs of mucosal edema, may also be seen
on radiographs. Mild or moderate ascites, which resolves after the acute attack,
may also be seen on ultrasound.79 Patients
typically are afebrile and have normal liver enzyme, bilirubin, amylase, and
lipase levels during acute episodes. White blood cell counts may be normal
or slightly elevated.
Ultrastructurally, gaps in the postcapillary venule endothelial cells,
as are typically seen with the actions of vasoactive substances, are seen
in tissue from affected areas.78 The resulting
edema has minimal cellularity.
MANAGEMENT
Although approximately a quarter of HAE cases occur as a result of spontaneous
mutations, most patients inherit the responsible mutation in an autosomal
dominant pattern. Thus, genetic counseling of affected individuals, as well
as their parents and siblings, is an important part of their overall treatment.
These relatives of the proband, as well as their offspring, should be tested
after genetic counseling is completed.
Where available, the treatment of choice for acute attacks of HAE or
AAE is intravenous purified, vapor-heated C1 esterase inhibitor concentrate.
If this is unavailable, then attenuated androgen administration (below) should
be started immediately, particularly when there is upper airway involvement.
After an infusion of C1 esterase inhibitor concentrate, serum levels of C1-INH
increase immediately, followed 2 to 24 hours later by a slower increase in
levels of C4.84 A randomized, placebo-controlled
trial84 of therapy with C1 esterase inhibitor
for acute attacks of HAE found that approximately 69% of acute attacks treated
with the concentrate responded completely within 30 minutes of the infusion,
and up to 95% of attacks responded within 4 hours. In comparison, only 12%
of those who received placebo had their attacks subside by 4 hours. Patients
who received C1 esterase inhibitor concentrate were monitored for 4 years
after completion of the study, and none developed seroconversion for any blood-borne
viral infection (human immunodeficiency virus and hepatitis B and C). Also,
none developed autoantibodies to C1-INH as a result of the infusion of concentrate.
Therapy with C1 esterase inhibitor concentrate is thus considered safe and
effective for the management of acute HAE attacks. Currently, C1 esterase
inhibitor concentrate is not available in the United States.
C1 esterase inhibitor concentrate, although recommended as the first
line of therapy for acute AAE exacerbations, is not as effective for this
condition as it is for HAE. The presence of large amounts of anti–C1-INH
autoantibodies, which rapidly inactivate infused C1 esterase inhibitor concentrate
in the serum of patients with type 2 AAE, is thought to be responsible for
this decreased efficacy.85 For type 1 AAE,
treatment of the underlying malignancy, lymphoproliferative or rheumatologic,
disorder may result in resolution of clinical and laboratory abnormalities.13 C1 esterase inhibitor concentrate was ineffective
in treating patients with the variant inherited angioedema.2
Intubation and ventilator support may be necessary for episodes associated
with severe respiratory tract compromise from laryngeal edema. Most reports
suggest that acute exacerbations of HAE or AAE typically do not respond to
administration of antihistamines, glucocorticoids, or epinephrine. However,
some researchers86 have reported success in
the acute management of AAE using these agents, probably owing to control
of the mast cell degranulation and histamine release. Proponents of this therapy
suggest administration of nebulized racemic epinephrine (1:1000 mixture) and
subcutaneous epinephrine (0.2-0.3 mL of 1:1000 concentration administered
every 20-30 minutes up to a maximum of 3 doses).23
Administration of epinephrine early in an attack seems to produce better results.
Symptomatic improvement has been reported for type 2 AAE using intravenous
methylprednisolone, 500 to 1000 mg daily.62
Use of attenuated androgens (17- alkylated androgens), such as
danazol and stanozolol, can prevent symptomatic attacks in patients with HAE.
Some patients with AAE, particularly type 1 disease, also respond to administration
of these agents. Patients with type 2 AAE typically derive little benefit
from androgen therapy. Androgens increase serum C1-INH, C4, and C2 levels.87-88 Methyltestosterone therapy is effective
in men. In an anecdotal study,89 oxandrolone,
a potent androgen, was used successfully as prophylaxis in a 13-year-old girl
who had failed prophylactic therapy with high-dose danazol and  -aminocaproic
acid. The patient's symptoms were controlled with a daily dose approaching
7 mg.89
Some authors90-91 suggest
that long-term prophylaxis should be offered to patients with 1 or more acute
exacerbations monthly. However, in a recent study,11
5 of 6 patients with HAE who asphyxiated had experienced no more than 3 exacerbations
per year. The risk of upper airway involvement, with the attendant risk of
asphyxiation, is high with each attack regardless of which organ system was
involved in previous attacks. Long-term prophylaxis should be considered in
any patient with a previous history of acute HAE affecting any organ system,
regardless of the number of previous attacks.
Attenuated androgens are used in the long-term prophylactic treatment
of male and female patients because they are effective and have relatively
mild adverse effects. Dosage ranges for danazol, stanozolol, and methyltestosterone
are 200 to 800 mg/d, 2 to 12 mg/d, and 10 to 30 mg/d, respectively. A typical
treatment regimen using the less expensive agent, stanozolol, is to start
adult patients at a dosage of 4 mg 3 times daily for the initial 12 weeks,
then tapering the dosage by 2 to 4 mg every 12 weeks until the lowest maintenance
dose that provides symptomatic relief is reached (typically 2-6 mg/d). An
alternative approach is to reduce the dosage as soon as symptomatic control
is achieved. Maintenance using alternate-day administration of stanozolol
is also effective. The lowest effective dose should be used for maintenance.
Attenuated androgens are efficacious in the prophylaxis of central nervous
system angioedema.15 Danazol doses as low as
200 mg every 2 or 3 days have been used successfully to reduce attack frequency.62 When surgery, dental manipulation, or another source
of trauma is planned, prophylactic treatment is necessary using danazol, 600
mg, daily for 10 days before surgery, or equivalent doses of another androgenic
agent.
The major contraindications to therapy with attenuated androgens are
pregnancy and lactation, prostate cancer, and childhood. Potential adverse
effects include increased hair growth, weight gain, seborrhea, acne, deepening
of the voice, vasomotor symptoms, decreased breast size, menstrual irregularities,
decreased libido, hepatic necrosis or cholestasis, hepatic neoplasms, hypertension,
and possibly increased atherogenesis resulting from abnormal lipoprotein metabolism.
Hepatocellular adenomas, and in one instance hepatocellular carcinoma, have
been reported in patients taking danazol for 10 or more years.92-93
Abnormal liver enzyme levels, from chronic hepatitis, have been shown not
to change significantly after initiation of therapy with these agents and
should therefore not be considered an absolute contraindication to their use.91 Stanozolol therapy seems to have fewer adverse effects
than does danazol therapy. Antiandrogens used in the treatment of prostate
cancer may decrease the efficacy of these therapies.
Intravenous administration of fresh frozen plasma (FFP), which contains
C1-esterase inhibitor, may help abort most episodes of acute HAE. However,
a paradoxical exacerbation of symptoms occasionally occurs presumably because
the excess C4 supplied in FFP acts as a substrate that fuels further tissue
damage. Consequently, FFP infusion is not recommended as therapy for severe
exacerbations, particularly for those already manifesting symptoms of laryngeal
edema. Prophylactic FFP infusion before surgery and dental extraction may
be useful in patients not receiving chronic prophylactic therapy with attenuated
androgens. Such infusions result in a small and transient increase in C1-INH
and C4 levels above baseline levels; however, this seems to be sufficient
in preventing acute attacks.9 Levels typically
return to baseline in 1 to 12 days. A typical regimen is to infuse 2 U of
FFP 12 to 24 hours before the procedure begins.
Antifibrinolytic agents (plasmin inhibitors), such as tranexamic acid
and -aminocaproic acid, are also used for prophylaxis against attacks;
however, these do not seem to be as effective as attenuated androgens in the
management of HAE. In children, antifibrinolytics have been used as first-line
drugs because of the adverse effects of attenuated androgens.7
These agents produce better results than do attenuated androgens when used
for long-term prophylaxis in AAE and may be used as first-line prophylactic
agents in patients with this condition.94-95
Some patients with AAE who did not respond or responded suboptimally to androgen
therapy may respond to adminstration of antifibrinolytic agents.23
After an initial oral loading dose of 5 g, typical dosages effective for management
of HAE have ranged from 7 to 10 g/d.9 Myalgia,
with or without elevated serum creatine phosphokinase or aldolase levels secondary
to rhabdomyolysis, is a potential adverse effect of therapy with this class
of agents.62 Muscle weakness, hypotension,
and fatigue may also occur with the use of high doses.
The use of antihistamines and epinephrine was ineffective in the treatment
of the variant angioedema. One patient responded to danazol therapy, whereas
another did not. Use of antifibrinolytic agents was also ineffective.2
Cytotoxic and immunosuppressive therapy (typically with cyclophosphamide)
and glucocorticoid therapy, with or without plasmapharesis, are beneficial
in decreasing autoantibody production in type 2 AAE, thereby alleviating symptomatic
attacks.13
Nafamostat mesylate, a serine protease inhibitor shown to exert inhibitory
activity on enzymes in the kallikrein-kinin system, has been used rarely to
treat HAE in Japan.69, 96 However,
its efficacy for this purpose has not been convincing.
Prophylactic administration of FFP, C1 esterase inhibitor concentrate,
or oral 17- alkylated androgens before any major surgical or dental
procedure is necessary to prevent an acute episode of HAE.
Angiotensin-converting enzyme inhibitors are contraindicated in patients
known to have HAE because they increase the half-life of bradykinin and can
thus precipitate symptoms.91 Oral contraceptive
agent use should also be avoided because it can precipitate attacks in some
individuals with HAE. Prophylactic administration of C1 esterase inhibitor
concentrate, FFP, or androgens should also be considered for affected individuals
before administration of intravenous radiologic contrast, streptokinase, or
tissue plasminogen activator because previous studies have suggested that
these agents may decrease levels of CI-INH in these patients.97-99
On occasion, acute attacks may recur frequently despite maximal maintenance
doses of attenuated androgens. In such instances, a search for ongoing environmental
triggers and chronic infections may be prudent. In a recent case report,100 eradication of H pylori
infection in a patient with recurrent acute HAE attacks unresponsive to 800
mg of danazol daily resulted in no further acute attacks and permitted a decrease
in the daily maintenance dose of danazol to 400 mg.
AUTHOR INFORMATION
Accepted for publication July 10, 2001.
Corresponding author: William J. Tremaine, MD, Division of Gastroenterology,
E19B, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
From the Divisions of Gastroenterology (Drs Nzeako and Tremaine), Hepatology
(Drs Nzeako and Tremaine), and Allergy (Dr Frigas), Mayo Clinic and Foundation,
Rochester, Minn.
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