ANGIOEDEMA

angioedema

Angioedema is an edematous area that involves inflammation in the dermis and

deeper subcutaneous tissue. It presents as non pitting swelling without any color
change. Skin angioedema swellings are usually pale and uncomfortable rather than
red and itchy.
The size of the angioedema varies, and although it can appear anywhere on the body,
it is most common in the periorbital and perioral regions.
Angioedema can also occur below mucous membranes of the mouth and genitalia.
In rare situations, it can affect the bowel and bladder causing pain due to obstruction
without being visible.
Because the deeper skin layers contain few mast cells, angioedema usually produces
little or no pruritus. In contrast to other forms of edema, angioedema is distributed
asymmetrically and does not characteristically occur in dependent regions.
angioedema
Angioedema may be a feature of urticaria where it is due to histamine release
from mast cells and responds to the same treatments as weals. It may also be a
feature of anaphylaxis if it causes choking as a result of swelling within the
throat.

If angioedema occurs without weals it may be caused by a completely different

mediator called bradykinin. It need completely different treatments from
urticaria. A proportion of patients with bradykinin-induced angioedema will
have inherited their condition. This is known as Hereditary Angioedema. 
About 50% of the children of affected patients are at risk of carrying the genetic
abnormality that results in a reduction in function of an important enzyme
inhibitor that controls several pathways necessary for good health.
 Angioedema and Urticaria
Angioedema accompanies in approximately
40% of patients with urticaria, another 40%
have hives alone, and about 20% have
angioedema but not urticaria.
HEREDITARY ANGIOEDEMA (HAE)

 HEREDITARY ANGIOEDEMA (HAE) IS A VERY RARE AND

POTENTIALLY LIFE-THREATENING GENETIC CONDITION THAT
OCCURS IN ABOUT 1 IN 10,000 TO 1 IN 50,000 PEOPLE.
 HAE symptoms include episodes of edema (swelling) in various body parts including the hands, feet, face and airway. In
addition, patients often have bouts of excruciating abdominal pain, nausea and vomiting that is caused by swelling in the
intestinal wall. Airway swelling is particularly dangerous and can lead to death by asphyxiation.
 HAE patients have a defect in the gene that controls a blood protein called C1 Inhibitor. The genetic defect results in
production of either inadequate or non-functioning C1-Inhibitor protein.
 Normal C1-Inhibitor helps to regulate the complex biochemical interactions of blood-based systems involved in disease
fighting, inflammatory response and coagulation.
 Because defective C1-Inhibitor does not adequately perform its regulatory function, a biochemical imbalance can occur
and produce unwanted peptides that induce the capillaries to release fluids into surrounding tissue, thereby causing
edema.
 If an episode of HAE involves laryngeal attacks this may lead to airway obstruction
and have the potential to cause death by asphyxiation. Amongst HAE patients
suffering from edema of the larynx, the estimated mortality rate of untreated attacks is
as high as 40 percent if the attack is not treated adequately. If the mucous membranes
in the larynx start to swell, immediate medical treatment is required. It may be
necessary to intubate the patient or make an emergency incision in the tracheotomy if
appropriate treatment is not available.
IMMUNOLOGICAL FEATURES

 Mechanism is thought to involve activation of the kinin system with bradykinin production, leading to tissue
oedema.
 ACE inhibitors inhibit bradykinin breakdown (also cause cough due to excess bradykinin).
 Histamine is not involved (unless there is accompanying urticaria).
 C1-esterase inhibitor is a control protein for the kinin cascade in addition to its role in the complement and
clotting systems.
 There are polymorphisms of this enzyme but it is not known whether they correlate with the tendency to develop
angioedema.
 Congenital ACE defi ciency has also been associated with angioedema.
 A child has a 50 percent possibility of inheriting this disease if one of the parents has it. The absence of family
history does not rule out the HAE diagnosis, however.
 Scientists report that as many as 20 percent of HAE cases result from patients who had a spontaneous mutation of
the C1-Inhibitor gene at conception. Consequently, these patients can pass the defective gene to their offspring.
 Because the disease is very rare, it is not uncommon for patients to remain undiagnosed for many years.
 A large number of patients report that their frequent and severe abdominal pain was inappropriately diagnosed as
psychosomatic, resulting in referral for psychiatric evaluation.
 Unnecessary exploratory surgery has been performed on patients experiencing gastrointestinal edema, because
abdominal HAE attacks mimic a surgical abdomen.
 Before therapy became available, the mortality rate for airway obstruction was reportedly as high as 30 percent.
 THERE ARE TWO SUBTYPES OF HAE BASED ON THE
UNDERLYING GENETIC DEFECT IN THE CONTROL OF THE
BLOOD PROTEIN C1-ESTERASE INHIBITOR (C1INH) – AND A
THIRD TYPE HAE WITH NORMAL C1INH.
 HAE TYPE I

Characterized by decreased levels of functional C1-INH protein; about 80-85 percent of patients suffer from this form
of the disease.
 HAE TYPE II

Associated with normal or increased levels of a dysfunctional C1-INH protein resulting in reduced levels of C1-INH
activity.
 HAE WITH NORMAL C1INH

A new form of hereditary angioedema (HAE). Arises independently of a C1-INH deficiency; it is relatively rare and
primarily affects women.
 Type I HAE and Type II HAE is caused by a defect (mutation) in the gene responsible for producing the protein
C1 esterase inhibitor (C1-INH). Unlike other hereditary diseases, the healthy gene cannot compensate for the
defect in the other gene in patients with HAE.
 Under normal conditions, C1-INH regulates the body’s production of bradykinin, a locally acting hormone that
plays an important role in the control of the dilation (widening) and permeability of blood vessels – for example,
in response to an injury or infection. If the C1-INH is not functioning properly or if its concentration is decreased,
bradykinin is released excessively resulting in local swellings.
 Besides the contact system, C1-INH is also involved in the so-called complement system, which is part of the
immune defense. As in the contact system, an external stimulus, for example a foreign body or microbe, triggers a
reaction cascade, which aims to eliminate the alien.
 The cascade starts with the protein C1, whose direct counterpart is C1-INH. C1 is activated as soon as the immune
system detects a foreign body, although the process is also self-activating to a lesser extent. Activated C1 activates
a series of other factors in the complement system resulting in the elimination of the pathogen.
 Infections, injuries, operations or stress may lead to consumption of C1-INH and may thus result in elevation of
bradykinin levels with subsequent edema formation. Drugs that lower blood pressure (ACE inhibitors) can also
cause edema: by inhibiting the degradation of bradykinin its level is increased.
 A new form of hereditary angioedema (HAE) with normal C1 inhibitor (C1INH) was first described in 2000. The
lack of clear diagnostic criteria, the heterogeneity among affected patients, and the varying names given to this
disease have led to substantial confusion among both physicians and patients. This [scientific proceedings] was
designed to bring more clarity to the diagnosis and potential treatment of HAE with normal C1INH. An
international symposium of experts was convened to review the field and develop consensus opinions that could
help clinicians who evaluate and manage these patients. Criteria were developed for the diagnosis of HAE with
normal C1INH in patients with recurrent angioedema in the absence of concurrent urticaria. In addition, potential
therapeutic strategies are discussed. The consensus criteria developed during this symposium will allow physicians
to better diagnose and treat patients with HAE with normal C1INH.
 HOW IS HAE DIAGNOSED?

Most cases of angioedema turn out to not be HAE, because most swelling attacks are typically allergic reactions or swellings
caused by something other than C1-inhibitor deficiency. Laboratory analysis of blood samples or genetic testing is
required to establish the HAE diagnosis.
 There are two specific blood tests that confirm HAE:
 C1-inhibitor quantitative (antigenic)
 C1-inhibitor functional
 The most common form of the disease – Type I – is characterized by low quantitative levels of C1-inhibitor and affects
about 85 percent of patients. Type II HAE affects the other 15 percent of patients who have normal or elevated levels of
C1-inhibitor, but the protein does not function properly.
 Several investigators have noted a familial (and therefore inherited) angioedema in patients with normal levels of C1-
inhibitor. Now found under the designation of “HAE with Normal C1 Inhibitor”, this form of angioedema is yet to be
fully understood. In women, swellings have been correlated with pregnancy or the use of oral contraceptives; however,
affected male family members have also been identified. Some scientists believe that a mutation in the gene for human
coagulation Factor XII may be a potential cause of swelling in these patients with familial estrogen-exacerbated
angioedema.
HEREDITARY C1 ESTERASE INHIBITOR DEFICIENCY
AT WHAT AGE DOES HAE ATTACKS START?

The age of HAE onset varies considerably, however, in one

study, half of the patients reported onset of their symptoms by
the age of seven, and over two-thirds became symptomatic by
the age of thirteen. There also seems to be an increased
frequency of attacks during puberty or adolescence.
TRIGGERS

 Episodes of HAE often occur without an obvious trigger. However, in some cases, a cause can be identified. For
instance, infections, minor injuries and mechanical stimuli such as pressure can induce an attack. Dental
procedures or surgery to remove the tonsils are particularly critical, as they can cause swelling in the larynx.
Emotional and mental stress can also trigger an attack.
Hormonal factors are another known cause of HAE attacks. For example, the frequency of episodes can be higher
in women taking products containing estrogen (the “pill”), products for menopausal complaints or who have their
menstruation.
 A class of blood pressure lowering drugs known as ACE (angiotensin-converting enzyme) inhibitors are
contraindicated in HAE patients as they have also been shown to trigger HAE attacks in some patients. HAE
patients should, therefore, avoid taking this type of medication.
HOW CAN HAE BE TREATED?

 UNTIL NOW, THERE IS NEITHER A CURE FOR PATIENTS WHO SUFFER FROM HAE ATTACKS NOR A
THERAPEUTIC CONCEPT TO PREVENT THESE ATTACKS COMPLETELY.
 Furthermore, in many countries, there are currently no acute attack treatments available for HAE patients. Here
physicians are therefore limited to providing patients with a short and long term prophylactic treatment with
attenuated androgens (such as Danazol and Oxandrolone) and in some cases tranexamic acid (such as Cyklokapron).
 Unlike allergic angioedema, HAE attacks do not respond to treatment with antihistamines, corticosteroids or
epinephrine. Current HAE treatment options focus on providing rapid relief during attacks or on the prevention of
symptoms in patients who experience a high frequency of attacks or who undergo dental or surgical procedures,
which may trigger an attack.
ACUTE TREATMENT

 The aim of acute treatment is to halt the progression of the edema and alleviate the symptoms. This applies
particularly to episodes affecting the larynx, which can cause death by suffocation if left untreated.
 The recommended options for acute treatment vary from country to country due to the fact that drugs for
specific treatment are not licensed in all countries. In these cases, acute treatment may be limited to more
unspecific drugs such as tranexamic acid or even just painkillers.
 In countries where it is available, C1-INH concentrate, Icatibant or Ecallantide can be used for the
treatment of acute attacks. Icatibant and Ecallantide must be administered by subcutaneous injection by a
healthcare professional; C1-INH concentrate must be administered intravenously.
LONG-TERM PROPHYLAXIS

 Long-term prophylaxis is given to patients whose quality of life is clearly reduced by HAE.
These are usually patients who have either very frequent or very painful attacks or are at high
risk of developing laryngeal edema.
 Long-term prophylaxis consists mainly of attenuated androgens, synthetically produced
derivatives of the male sex hormone testosterone. They can reduce the number of attacks, but
as these medications are associated with a range of severe side effects, attenuated androgens
are generally reserved for patients suffering from frequent and/or severe symptoms.
 In some countries, antifibrinolytic drugs such as tranexamic acid or aminocaproic acid are
used as alternative to androgens.
SHORT-TERM PROPHYLAXIS

 Short-term preventative therapy is recommended for patients undergoing dental procedures or surgery,
which have been known to trigger an attack. One option for short-term prophylaxis consists of high
dose androgen therapy for at least five days prior to surgery and four days afterwards. Where available,
another option is to administer C1-INH concentrate one to two hours prior to surgery.
 TREATMENT OF ACUTE ATTACKS

 Angioedema seen in HAE does not respond to the drugs employed in treating other forms of
urticaria/angioedema such as antihistamines, epinephrine and corticosteroids. While epinephrine, in
particular, may have a transient effect on swelling, it does not alter the course of an attack.
 Maintaining airway patency is the primary concern for patients with laryngeal edema. If the airway is
threatened, an experienced physician should intubate the patient. In addition, the capability for
emergency tracheotomy should be readily available. Because gastrointestinal edema usually involves
excruciating pain, frequent vomiting and the potential for hypotension, therapy should include
aggressive fluid replacement and pain management. Clinicians report that Zofran, Compazine and
Phenergan are effective in reducing nausea and vomiting, while morphine or other narcotics are
routinely used to relieve attack related abdominal pain. Some physicians use fresh frozen plasma in the
acute attack setting, but this therapy is considered controversial because in addition to C1-inhibitor,
fresh frozen plasma contains substrates of the complement and kinin systems that could produce a
vasoactive peptide and cause an attack exacerbation.
HAE DURING PREAGNANCY

 Women with HAE can have children as HAE does not impair fertility. However, women who are being treated
with androgens should stop taking them, as this treatment can impair female fertility.
 Episodes of HAE can increase or decrease during pregnancy, as can the severity of the edema. Your doctor will
follow you closely during this time and discuss appropriate treatment with you.
 The defect on chromosome 11 that is responsible for HAE is equally common in men and women and can be
passed on by both sexes.  As HAE is an autosomal dominant hereditary disease, there is a 50 percent risk of a
child inheriting the disease from the affected parent. Male and female offspring are at equal risk of inheriting
HAE.
COPING

Whilst effective treatments are now available for emergencies, the condition can still
be stressful for patients because attacks are unpredictable and medical help may be
required at very short notice. Because severe attacks of both bradykinin and
histamine-induced angioedema involving the throat require injections, patients
need to be shown how to self-administer treatment and gain confidence in how to
manage an emergency effectively. Less severe attacks settle naturally over days
but still cause discomfort and embarrassment if they are on the face and may be a
reason for taking days off work or school.
QUESTIONS ?