Angioedema
Definition
Angioedema (AE) is a deep, localized
and self‐limiting swelling of the skin and submucosal tissues due to
a temporary increase in vascular permeability resulting from vasoactive
mediators. AE without weals should be considered separately from AE with
weals. AE without weals is an uncommon but very important bradykinin‐induced angioedema, including hereditary angioedema (HAE)
which is inherited as an autosomal dominant disorder, whereas AE with weals
falls within the spectrum of spontaneous or inducible urticarias resulting from
mast cell degranulation. Bradykinin‐induced
AE may cause fatal laryngeal or bowel obstruction, sometimes presenting as an
acute abdomen. Mast cell mediator‐induced
angioedema, by comparison, is a common presentation of spontaneous urticaria
and may occur without weals. It affects the skin, and/or oropharynx but
laryngeal involvement is exceptional and the bowel is never affected. The
different types of angioedema presenting without weals:
|
Mast cell mediator induced |
Bradykinin induced |
|
Chronic spontaneous urticaria ·
Known causes (autoreactivity, infection, food intolerance) ·
Unknown cause (idiopathic) |
Hereditary angioedema (HAE) ·
Type I (C1INH
concentration low) ·
Type II
(C1INH activity low) ·
HAE with
normal C1INH (type III) |
|
Chronic inducible urticarias (only rarely present with pure angioedema), e.g. ·
Vibratory angioedema ·
Cholinergic
urticaria |
Acquired angioedema ·
Acquired
C1INH deficiency ·
Drug induced
(e.g. ACE inhibitor) ·
Idiopathic
non‐mast cell mediator‐induced
angio‐edema |
Classification of angioedema without
wheals
Classification of angioedema by endotypes
Introduction
Angioedema without weals involves
the subcutaneous and submucosal tissues, rather than the dermis. Almost any
part of the body may be involved, but the most common sites are the lips,
eyelids and genitalia due, in part, to the laxity of the dermal and
subcutaneous tissues at these sites. The tongue and pharynx may also be
affected, but this is much less common in mast cell mediator‐induced angioedema than bradykinin‐induced angioedema. Individual lesions may be either single
or multiple and may appear suddenly. Itching is often absent. The lesions last
from a few hours to several days.
Angioedema,
hereditary
This is a rare disorder, accounting
for less than 2% of all cases of angioedema without weals. A family history is
usually, but not always, apparent since up to 25% of cases appear to result
from a de novo mutation of the gene controlling C1INH (SERPING1).
HAE is divided into three types: type I have reduced C1INH; type II have normal
or raised levels of C1INH that is functionally inactive; and a more recently
described third type of HAE with normal C1INH, formerly known as HAE type III,
has normal levels of immunochemical and functional C1INH and is diagnosed
mainly on a positive family history.
Epidemiology
Incidence
and prevalence
Mast cell mediator‐induced angioedema is by far the commonest presentation of angioedema
without weals, representing up to 10% of patients with spontaneous urticaria,
thus it is much commoner than HAE. ACE inhibitor‐induced
angioedema affects up to 1% of patients on treatment. HAE affects approximately
1: 50 000 of the general population. Acquired C1INH deficiency is extremely
rare; its prevalence is unknown.
Age
Mast cell mediator‐induced angioedema can present at any age but more often in
the fourth or fifth decades of life in line with chronic spontaneous urticaria.
Over 75% of patients with HAE will have had their first attack by the age of 15
years although onset may be delayed until adult life. ACE inhibitor‐induced angioedema is predominantly a problem of older
people requiring antihypertensive treatment.
Sex
Mast cell mediator‐induced angioedema and ACE inhibitor‐induced angioedema are more common in women. There is no sex
bias for HAE types I or II, but HAE with normal C1INH presents mainly in women.
Associated
diseases
Mast cell mediator‐induced angioedema is associated with thyroid autoimmunity
in common with spontaneous urticaria.
Pathophysiology
Bradykinin formation and breakdown. Bradykinin is formed
predominantly from high‐molecular‐weight kininogen (HMWK) by plasma kallikrein. Binding of
bradykinin to the B2 receptor (B2R) on the endothelium of small blood vessels
causes vasodilatation and vasopermeability. Bradykinin is broken down by a
multistage process primarily involving angiotensin‐converting enzyme (ACE), also known as kininase II. LMWK,
low‐molecular‐weight kininogen.
Environmental
factors
All types of HAE are aggravated by estrogen
in contraceptive and hormone replacement therapies but not non‐steroidal anti‐inflammatory
drugs (NSAIDs).
Clinical
features
Mast cell mediator‐induced angioedema
The presentation of mast cell
mediator‐induced angioedema without weals is the same as angioedema
that presents in patients with spontaneous urticaria who also exhibit weals.
Oro‐pharyngeal involvement is unusual and laryngeal edema is
exceptional. Abdominal angioedema does not occur.
Drug reactions
A number of
drugs can cause angioedema without wheals. The most common are NSAIDs and ACE
inhibitors. Aspirin intolerance may present with angioedema alone, or with
urticaria or anaphylaxis; cross-reactions with other NSAIDs can occur.
ACEI-induced angioedema
ACEIs
have a special ability to cause angioedema, nearly always without associated
weals. The mechanism is thought to relate to the ability of ACEIs to prolong bradykinin
survival and potentiate its effects by inhibiting ACE, also known as kininase
II. Most cases develop within 3 weeks of commencing treatment, but can occur at
any time during treatment, even years after starting. It is a class effect seen with all ACE inhibitors. Angioedema affects
the face and oropharynx predominantly.
Symptoms may be severe, and laryngeal involvement may be life threatening. Abdominal symptoms are rare. Intravenous antihistamines and
corticosteroids have been used, sometimes repeatedly, and epinephrine
injections should be given if swelling involves the airway, although the
development of a bradykinin receptor antagonist, icatibant, is more effective
and become the treatment of choice. Reactions are more likely to occur if the
patient has had previous episodes of angioedema, has ACEI induced cough or has
hereditary angioedema. For practical purposes, ACE
inhibitors should be discontinued in favor of other antihypertensive
medications if angioedema occurs without wheals. The angiotensin II receptor
antagonists (‘sartans’) should also be prescribed with caution since angioedema
has also been described in a few patients previously intolerant of ACEI, but
probably by another mechanism that has been proposed to involve nitric oxide
release with potentiation of the effects of bradykinin. ACE inhibitors are contraindicated in patients with HAE and
acquired C1 inh deficiency. ACE inhibitor‐induced
angio‐edema remits after discontinuation of the drug but may take
up to 6 months to subside after stopping. The reason for this is unknown.
Hereditary angioedema
The clinical picture of HAE usually
facilitates strong suspicion of the diagnosis before laboratory confirmation.
There are recurrent swellings of the skin and mucous membranes throughout life,
often associated with nausea, vomiting, colic and urinary symptoms. These
attacks may occur regularly every few days or weeks, or may be less frequent.
Abdominal symptoms may occur in the absence of skin changes and cause great
diagnostic difficulty. Pharyngeal, laryngeal and even bronchial involvement,
are especially significant and dominate the prognosis. The skin and mucosal
lesions are often solitary and may be painful. They seldom itch and they may
occur spontaneously or after trauma; dental trauma and intubation being
especially hazardous. Weals do not occur, but many patients exhibit a rather
distinctive reticulate erythema, perhaps with minimal edema, which occurs
prodromally (‘Chicken‐wire’ reticulate erythema/urticaria, non‐pruritic, on the trunk).
Chronic mast cell mediator‐induced angioedema usually lasts for several months to
years. Spontaneous resolution is the rule. HAE is lifelong with variations in
activity corresponding to environmental factors, lifestyle, drugs (especially
exogenous estrogens and ACE inhibitors) and endogenous factors (e.g. puberty
and pregnancy). The main risk of HAE is suffocation and death. Treatment of the
underlying B‐cell lymphoproliferative disorder may lead to resolution of
type 1 acquired C1INH deficiency. ACE inhibitor‐induced
angioedema remits after discontinuation of the drug but may take up to 6 months
to subside after stopping. The reason for this is unknown.
Investigations
In patients with mast cell
activation‐induced angioedema, spontaneous and inducible forms should
be considered. They can occur in the same patient. Severe inflammatory
disorders should be ruled out by checking C‐reactive
protein (CRP) and a white blood cell differential. Patients with frequent
attacks and/or long standing disease should be checked for underlying causes.
C4 complement is a good
screening blood test for HAE types I and II, especially during attacks. It
should be less than 30% of mean normal in affected patients. Measurement of
functional C1INH is necessary to diagnose type II HAE. Both C4 and
C1INH will be normal in HAE with normal C1INH (type III). C4 and
functional C1INH are low in acquired C1INH deficiency and C1q is also reduced.
Management
The management of mast cell mediator‐induced angioedema is essentially the same as for chronic
spontaneous urticaria patients with weals, except that oropharyngeal lesions may occur and cause great distress. Non‐sedating, second‐generation
H1 antihistamines are the first line treatment. They should be used
on a daily basis until spontaneous remission. Higher than standard doses (up to
fourfold) may be required to achieve sufficient protection. Omalizumab (anti‐IgE) is licensed for the use of antihistamine refractory
cases of chronic spontaneous urticaria and should be considered as third line
therapy. Emergency treatment with epinephrine is discussed along with
anaphylaxis.
The
treatment of recurrent angioedema due to C1INH deficiency is completely
different. H1 antihistamines, steroids and epinephrine are
ineffective for HAE or acquired C1INH deficiency. Estrogen therapies, such as
the oral contraceptive pill, and ACE inhibitor may induce or exacerbate HAE and
should be avoided. Management should be considered under emergency treatment of
an established attack, short‐term
and long‐term prophylaxis.
Treatment summary for angioedema
without weals
Mast cell mediator‐induced angio‐edema
·
As
for chronic spontaneous urticaria
Bradykinin‐induced angio‐edema
Hereditary types
I, II
Hereditary angio‐edema with normal C1INH (type III)
Emergency
§ Icatibant (bradykinin
receptor 2 antagonist)
§ Plasma‐derived
C1INH
Short‐term
prophylaxis
§ Plasma‐derived
C1INH
Long‐term
prophylaxis
§ Plasma‐derived
C1INH
Acquired C1INH deficiency
Emergency
§ Plasma‐derived
C1INH
§ Icatibant (bradykinin
receptor 2 antagonist)
Prophylaxis
§ Plasma‐derived
C1INH
§ ACE inhibitor‐induced
angio‐edema
§ Stop and avoid all
ACE inhibitor
|
|
Emergency
treatment of hereditary angio‐edema
Purified plasma‐derived C1INH (pdC1INH) given by bolus intravenous infusion
per body weight has been the primary treatment for oro‐facial or laryngeal edema and abdominal colic for three decades.
Twenty units/kg body wt is now recommended. Self‐administration
by patients at the first sign of an attack is now encouraged since it leads to
more rapid resolution of symptoms and less risk of progression of swellings.
Symptom relief should be seen within 30–90 min of infusion but it may take 6–8
h for complete resolution. Icatibant, a bradykinin receptor II antagonist, is
now also available and may be the treatment of choice since it is given by
subcutaneous injection and has similar efficacy to C1INH concentrate.
Treatment
of acquired C1‐esterase
inhibitor deficiency
Icatibant and C1INH are the
treatment of choice.
