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Symposium: The Spectrum of Chronic Urticaria and Angioedema
The spectrum of chronic angioedema
Aleena Banerji, M.D.,* and Albert L. Sheffer, M.D.#
ABSTRACT
This article focuses specifically on angioedema. Chronic angioedema represents a wide range of diseases and can be
categorized into several forms including hereditary, acquired, drug induced, and idiopathic. Hereditary and acquired
angioedema are known to be a result of abnormalities in C1 inhibitor protein while the mechanism of drug-induced and
idiopathic angioedema is less clear. Significant advances have been made in recent years with regard to diagnosis and
management of these patients leading to a significant reduction in morbidity and mortality. Several novel therapies are
in clinical trials and should be available in the United States within the next year. There is still a lot to learn about the
pathophysiology, diagnosis, and treatment of patients with chronic angioedema. This review will hopefully provide more
information to the readers who care for patients with these disorders and also stimulate further interest and research into
the pathophysiology of these conditions.
(Allergy Asthma Proc 30:11–16, 2009; doi: 10.2500/aap.2009.30.3188)
Key words: ACE inhibitors, androgens, angioneurotic, bradykinin, C1 inhibitor, hereditary, idiopathic, kallikrein,
swelling
A
ngioedema is defined as nonpruritic, nonpitting
areas of swelling of cutaneous and mucosal tissues and usually affects the deeper skin layer. Urticaria, or hives, is swelling of the superficial skin layer.
In the clinical setting, patients can present with angioedema alone, urticaria alone, or a combination of urticaria and angioedema. Angioedema can be categorized
into several forms: hereditary, acquired, associated
with allergic reactions (i.e., venom hypersensitivity,
latex allergy, adverse drug reactions, and food allergy),
and idiopathic.
The hereditary and acquired forms of angioedema
are more chronic in nature and not associated with
urticaria. This type of isolated angioedema without
urticaria is frequently bradykinin mediated and, thus,
not responsive to antihistamines. Angioedema associated with allergic reactions is often not chronic and is
associated with urticaria that is usually responsive to
antihistamine therapy. Idiopathic angioedema repre-
From the *Division of Rheumatology, Allergy, and Immunology, Massachusetts
General Hospital, Harvard Medical School, Boston, Massachusetts, and #Division of
Rheumatology, Allergy and Immunology, Brigham and Women’s Hospital, Harvard
Medical School, Boston, Massachusetts
Presented at the Eastern Allergy Conference, Naples, Florida, May 1, 2008
Supported by an educational grant from Sanofi-Aventis Pharmaceuticals and UCB
Pharma
Address correspondence and reprint requests to Aleena Banerji, M.D., Massachusetts
General Hospital, 100 Blossom Street, Cox 201, Boston, MA 02114
E-mail address: [email protected]
Copyright © 2009, OceanSide Publications, Inc., U.S.A.
sents a wide spectrum of disease with varying degrees
of severity and chronicity. This review focuses specifically on chronic angioedema.
HEREDITARY ANGIOEDEMA
Introduction
Hereditary angioedema (HAE) was first described in
1840.1 In 1882, the term angioneurotic edema was assigned to these patients to describe the observed effect
of mental stress on exacerbations in this disease.2 The
autosomal dominant nature of this disease was identified in 1888 based on observations in each of five
generations of a family.3 It was not until the early 1960s
that the pathophysiology of HAE was better understood when the absence of C1 inhibitor4 and the deficiency of a kallikrein inhibitor5 was described in these
patients.
The prevalence of HAE in the literature ranges from
1:10,000 to 1:50,000.6 HAE is categorized into types I
(80 – 85% of cases) and II (15–20% of cases). Types I and
II are reported in all races with no sex predominance,
which is not surprising based on its autosomal dominant inheritance pattern. Although it is often inherited,
20 –25% of cases are from new spontaneous mutations.
To date, ⬎150 mutations have been identified in the C1
inhibitor gene.7 Both types of HAE have low C4 levels
(although in rare cases the C4 can be normal), but type
I HAE is associated with a low C1 inhibitor level and
an abnormally functioning C1 inhibitor. Type II HAE,
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Table 1 Laboratory abnormalities in hereditary angioedema (HAE), acquired angioedema (AAE), and
angiotensin-converting enzyme (ACE) inhibitor–associated angioedema
Diagnosis
C4
C1 Inhibitor Function
C1 Inhibitor Level
C1q
HAE type I
HAE type II
AAE
ACE inhibitor–associated
angioedema
Low
Low
Low
Normal
Low
Low
Low
Normal
Low
Normal
Normal/low
Normal
Normal
Normal
Low
Normal
on the other hand, often has normal levels of C1 inhibitor with a poorly functioning C1 inhibitor (Table 1)
protein. A low C2 level may be found during an acute
attack of HAE.8
Pathophysiology
The pathophysiology of HAE is characterized by a
deficiency in C1 inhibitor. C1 inhibitor regulates the
activation of the complement system and the contact
system and seems to play a smaller role in the regulation of fibrinolysis and coagulation. The first classic
pathway complement component, C1, is composed of
three proteins, viz., C1q, C1r, and C1s. C1 inhibitor is
the only protein that can inactivate both C1r and C1s
and is therefore the primary regulator of the classic
pathway.7,9 C1 inhibitor also plays a role in the inhibition of the other complement pathways via inhibition
of manose-binding lectin associated serine protease-1
and -2. Thus, low levels of or a poorly functioning C1
inhibitor leads to unopposed activation of the complement system via C1. Regarding the contact system, C1
inhibitor is known to inactivate plasma kallikrein, factor XIIa, and plasmin. Although ␣2-macroglobulin is
known to inhibit the activation of these proteins, C1
inhibitor remains the major regulator. Thus, the lack of
inhibition via C1 inhibitor leads to persistent activation
of the contact system and increased levels of bradykinin (Fig. 1). Bradykinin is the nanopeptide known to
increase vascular permeability leading to angioedema
in these patients.5,7
festation. Most patients have a prodrome and can recognize several hours in advance that an attack is starting. Common triggers can include trauma, stress,
infection, menstruation, oral contraceptives, hormonal
replacement therapy, and angiotensin-converting enzyme (ACE) inhibitors.
Pregnancy has been associated with a decrease in
serum C1 inhibitor and can worsen symptoms. However, pregnancy can be associated with a decrease in
attack frequency. This can be explained by the fact that
the total amount of C1 inhibitor may actually increase
during pregnancy. HAE patients have been found to
experience premature labor more often than unaffected
family members.11–13
Clinical Presentation
Angioedema can involve any part of the body, but
often presents as swelling of the face, lips, tongue,
abdomen, larynx, extremities, and sometimes the genitals. Angioedema may involve the gastrointestinal
tract, leading to intestinal wall edema, which results in
symptoms such as abdominal colic, nausea, vomiting,
and diarrhea. At least 50% of HAE patients have a
laryngeal attack at some point during their lifetime.10
The swelling is nonpruritic and usually lasts 3–5 days
before gradual resolution. Patients do not have associated urticaria, but can have a serpiginous rash known
as erythema marginatum often as a prodromal mani-
Treatment
Attenuated androgens are the main class of medications used for many years for the short- and long-term
treatment of patients with HAE.14 However, the adverse effects of the attenuated androgens including
hirsutism, weight gain, seborrhea, acne, deepening of
the voice, decreased breast size, menstrual irregularities, decreased libido, hepatic necrosis, cholestasis, hepatic neoplasms, hypertension, and abnormal lipoprotein metabolism6 have often been of concern. Periodic
monitoring of liver function tests and lipid profiles is
recommended in any patient on long-term therapy
with androgens. Treatment regimens in many of the
12
Figure 1. Role of C1 inhibitor in the complement and contact
systems.
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previously published studies of attenuated androgens
typically start with high doses of androgens and taper
down the dose every few weeks until the lowest maintenance dose that provided symptom control is
reached. Alternatively, treatment with lower doses can
be initiated with a progressive increase of the dose
until symptoms are controlled and adverse effects are
minimized. Antihistamines and corticosteroids have
not been found to be helpful in treatment symptoms.
The use of fresh frozen plasma in acute HAE attacks
remains controversial.
The management of HAE must address the abrogation of acute episodes of angioedema and short- and
long-term prophylaxis.15,16 Purified C1 inhibitor concentrate is very effective in treating patients with HAE.
Unfortunately, there are no drugs, including C1 inhibitor concentrate, approved to date in the United States
for the treatment of acute episodes,15 although there
are many in clinical trials nearing Food and Drug
Administration approval.17 These products in phase III
clinical trials for the acute treatment of HAE include
icatibant, a bradykinin receptor antagonist, and DX-88,
a kallikrein inhibitor, along with two purified C1 inhibitor products and a recombinant C1 inhibitor product. Each of these products plays in role in inhibiting
the generation of bradykinin.
Other Types of HAE
The term type III HAE has often been used to describe a new group of patients with the classic symptoms of HAE but without any abnormalities in C4 or
C1 inhibitor. It was initially described only in women
and felt to be estrogen related and has led to some
using the terms estrogen related or estrogen dependent.8 More recently, a specific mutation in factor XII
has been described in some of these patients.18 Interestingly, estrogen has been found to up-regulate this
gain of function mutation in factor XII.18
A recent report19describes homozygous C1 inhibitor
deficiency. The two homozygous patients, rather than
failing to secrete C1 inhibitor, produced low levels of a
poorly functioning C1 inhibitor protein. These patients
had extremely low or absent levels of C1q, a finding
different from the usual HAE patient with one mutant
gene who has normal levels of C1q. The number and
severity of angioedema attacks were very low in one
patient and absent in the other patient; so, this appears
to be a syndrome that may be different from the usual
heterozygous HAE. In addition, their complement profile resembles a patient with acquired angioedema
(AAE) rather than the usual HAE patient.
ACQUIRED ANGIOEDEMA
AAE was first described in a patient with lymphoproliferative disorder in 1972.20 A few years later, in
1986, the autoimmune nature of the disease was described in a patient found to have an autoreactive IgG
against C1 inhibitor.21 The pathophysiology of this
disease arises from rapid consumption of C1 inhibitor
and loss of inhibition of the complement cascade leading to angioedema.
To date, there have been close to 140 cases of AAE
(also known as acquired C1 inhibitor deficiency) described in the literature.22 Non-Hodgkin’s lymphoma
was found in 20% of these patients and monoclonal
gammopathy was in 35% of these patients. Other nonhematologic neoplasms, infections, and a variety of
autoimmune diseases have also been found to be associated with AAE. This has led to the separation of
AAE into two groups. AAE type I is associated with
lymphoproliferative diseases or paraneoplastic syndromes. AAE type II is associated with autoimmune
disease and these patients often have autoantibodies to
C1 inhibitor.
The clinical presentation of AAE mimics that of patients with HAE and is clinically difficult to distinguish
on symptoms alone. These patients differ from HAE by
an absence of a family history of angioedema and a
much later onset of symptoms, usually in the fourth
decade of life or later. Patients with AAE have low
levels (or activity) of C1 inhibitor, C4, and C1q. A low
C1q along with an associated lymphoproliferative disease or autoimmune disease can help differentiate
AAE from HAE.
Successful treatment of the underlying disease often
leads to resolution of angioedema symptoms and biochemical abnormalities, but there are exceptions. Some
patients may continue to have persistent biochemical
abnormalities after treatment of the underlying disease
but no clinical symptoms. In other patients, disappearance of angioedema may be temporary even without
evidence of recurrent paraneoplastic disease.
DRUG-INDUCED ANGIOEDEMA
ACE inhibitors are the most common class of medications associated with isolated angioedema. However, we must also consider angiotensin receptor
blockers, aspirin, NSAIDs, narcotics, antibiotics, IL-2,
oral contraceptives, and interferon-␣ in our differential
of medications associated with angioedema, although
patients with adverse reactions to some of these other
medications can present with a combination of urticaria and angioedema.
The incidence of angioedema from ACE inhibitors
ranges in the literature from 0.1 to 2.2%.23,24 Angioedema from ACE inhibitors has a predilection for the
face, tongue, and lips. Incidence of ACE inhibitor angioedema is highest in the first month of treatment, but
can occur years later. There is a higher risk of angioedema in African Americans, patients with HAE,
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13
women, smokers, and older age while diabetics seem
to have a lower risk.25
The number of patients on ACE inhibitors continues
to rise, leading to increasing rates of angioedema.26 In
2001, there were 35– 40 million prescriptions written
for ACE inhibitors worldwide,27 and in 2007, ACE
inhibitors remain the most frequent class of medications prescribed for the treatment of hypertension.28
They are the most common class of medications associated with angioedema presenting to the hospital and
emergency department.29 Although fatalities are exceedingly rare, patients may still need inpatient hospitalization and intensive care treatment for management of respiratory compromise and upper airway
angioedema.
The mechanism of ACE inhibitor-induced angioedema remains unclear but may be related to increases
in bradykinin levels.30,31 Bradykinin would normally
be degraded by ACE, but its degradation by ACE is
inhibited by ACE inhibitors. Other enzymes such as
aminopeptidase P would degrade bradykinin in the
presence of ACE inhibitors, but have also been reported to be deficient in patients with ACE inhibitor–
induced angioedema, suggesting a possible cause of
the angioedema.32 If elevated bradykinin levels or decreased degradation of bradykinin are the main causes
of ACE inhibitor–induced angioedema, then current
treatments (including antihistamines, corticosteroids,
and epinephrine) will presumably not be helpful.33
Rather, newer agents such as bradykinin receptor antagonists or kallikrein inhibitors may provide novel
alternatives for the treatment of ACE inhibitor–induced angioedema. These medications are currently
under development for HAE and do not have Food
and Drug Administration approval.34,35 Substance P
accumulation as a result of low levels of dipeptidyl
peptidase IV levels leading to an alternative explanation for ACE inhibitor-induced angioedema has also
been proposed,36 but the exact mechanism leading to
ACE inhibitor–induced angioedema is not known.
Current treatment options are very limited and focus
mainly on supportive care and discontinuation of the
ACE inhibitor. Additonal research into the exact mechanisms of ACE inhibitor–induced angioedema and development of novel treatment options are still needed.
IDIOPATHIC ANGIOEDEMA
Idiopathic angioedema is a diagnosis of exclusion
after a thorough evaluation. It is often defined as three
of more episodes of angioedema in a period of 6 –12
months without a clear etiology.37 Idiopathic angioedema is felt to be the most common cause of chronic
angioedema, but the true epidemiology is not known.
Aside from what we discussed earlier in this article
including HAE, AAE, and drug-induced angioedema,
14
the differential diagnosis should also include allergic
conditions such as food allergy, latex allergy, and less
common conditions such as episodic (Gliech’s syndrome) and nonepisodic angioedema with eosinophilia (EAE and NEAE, respectively) and idiopathic
capillary leak syndrome (Clarkson syndrome).
EAE was first described in 1984.38 Although several
hypotheses have been proposed, the exact etiology
remains unclear. The main hypothesis suggests a role
for helper T cells leading to an increase of cytokines
including granulocyte monocyte colony-stimulating
factor,39 IL-3, IL-5,40 and IL-6.41 EAE is characterized
by recurrent episodes of angioedema, urticaria, pruritus, fever, weight gain, elevated serum IgM,42 oliguria,
and leukocytosis with peripheral blood eosinophilia
and eosinophil degranulation in the dermis. Episodes
usually occur every few weeks to months with complete resolution of symptoms between episodes. EAE is
rare and can be difficult to diagnose but has a good
prognosis with no visceral organ involvement. Lowdose oral steroids are felt to be the best initial treatment
for EAE.43
NEAE was first proposed in 198844 as a separate entity
from EAE because it was less severe and usually was
limited to one attack. NEAE should be considered in
patients, particularly women, who present with edema of
bilateral upper or lower extremities and eosinophilia
without urticaria. NEAE is responsive to low-dose corticosteroid or antihistamine therapy,42,44,45 but often no
treatment is needed because spontaneous remission frequently occurs.46 This is in contrast to EAE, where spontaneous remission without any treatment is rarely seen.
Idiopathic capillary leak syndrome is a rare syndrome that was first described by Clarkson in 1960.47
Attacks vary in frequency, severity, and duration, but
can be life-threatening with a 5-year mortality rate of
70 – 80%.48 This syndrome usually affects individual’s
aged 30 –50 years with a mean age of 46 years.49
Marked thirst is described early in the attack with
subsequent muscle weakness, abdominal pain, nausea,
and vomiting with generalized edema. Generally, the
edema appears several hours or days before the onset
of acute renal failure, pulmonary edema, and shock.
This is often associated with hypoalbuminemia, rhabdomyolysis, and monoclonal gammopathy. In addition
to plasma expanders and steroids, terbutaline, epoprostenol, salbutamol, loop diuretics, calcium antagonists
and Gingko biloba extract have also been reported to
show some success.50 –52 C1 esterase inhibitor therapy
has also been reported to be successful in a small
number of patients and is thought to decrease symptoms via early inactivation of the complement and contact systems.53 The underlying cause is not fully understood, but this disorder is believed to be due to an
alteration of endothelium permeability leading to a
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rapid shift of plasma form the intravascular to the
extravascular compartment.51
Evaluation of a patient suspected of having idiopathic angioedema should include a comprehensive
physical exam with a detailed personal and family
history, food, or latex skin testing if appropriate, and
additional labs including C4, C1Q, C1 inhibitor, CBC,
serum protein electrophoresis, IgE, and erythrocyte
sedimentation rate. One may want to consider a skin
biopsy for further evaluation if underlying vasculitis is
suspected.
There is still much to be learned about the pathophysiology, diagnosis, and treatment of patients with
angioedema. Our hope is that this review will be of
help to those readers who care for patients with these
disorders and will stimulate interest in further research
into the pathophysiology of these conditions.
14.
15.
16.
17.
18.
19.
20.
21.
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