German Society for Angioedema Research |
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German Society for Angioedema Research |
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Hereditary angioedema (HAE) occurs in two forms: in the first and most common form (85% of patients) there is a defect of synthesis of C1-INH, which is greatly reduced in quantity. The second form (15% of patients) is based on a dysfunction of C1-INH, the plasma concentration of which is normal or even increased. HAE becomes manifest most frequently in the second or sometimes even the first ten years of life whereas acquired angioedema due to C1-INH deficiency nearly always starts in adulthood. Later in life i.e. after the age of 60, episodes of HAE often follow a course with milder symptoms.
The
main symptoms are circumscribed skin swellings of the limbs, face,
and trunk as well as colicky recurrent pains in the abdomen, and,
in rare cases, sudden obstruction of the upper airways. Other
organs are only involved rarely.
Preceding
or accompanying uncharacteristic non-itching macular rashes,
gyrate erythema or annular-serpiginous exanthema are sometimes
reported by the patients. The skin swellings are virtually never
accompanied by pruritus but only by a sensation of tension and
more rarely by pain. The extremities are affected in virtually
all patients, the face in about 85%. On the average, they last
for one to three days but may subside after only a few hours or
after seven days. The duration, extent, and location of the
swellings can vary widely in the same patient.
The
abdominal pain attacks become manifest alone or combined with
skin changes. About two-thirds of all patients exhibit
gastrointestinal symptoms; the most common of which are colicky
pains and nausea; retching and vomiting may occur. During an
episode of this kind, which usually lasts for 2-7 days, watery
diarrhea may be experienced as a result of fluid accumulation in
the lumen of the edematous intestinal tract. Often, transient
ascites has been reported. In some patients solely the abdominal
symptoms may occur.
Laryngeal
edema may occur spontaneously or may follow trauma of the buccal
cavity or pharynx, especially dental surgery or tonsillectomy.
Edemas of the larynx and glottis begin with difficulty to swallow,
voice changes and hoarseness before dyspnea sets in. Asphyxiation
is possible. Laryngeal edemas frequently occur alone. In some
patients the attack may first begin with skin swellings for
example in the face or on the extremities, which are then
followed by laryngeal edema. At the beginning of a glottal or
laryngeal edema, treatment and preparations for intubation, which
may become necessary, or even tracheotomy must be started
immediately.
The factors that trigger an attack include trauma such as injections, abdominal surgery, dental surgery, tonsillectomy as well as injuries and minor trauma. In addition, patients have reported anxiety, mental stress and localized infections as a cause. Severe and prolonged mechanical stress to the extremities may result in edema of the limbs.
Patients with hereditary angioedema due to C1-INH deficiency may have auto-immune diseases such as lupus erythematosus.
Before appropriate monitoring and prophylactic long-term drug therapy was possible, the mortality rate was up to 30%. The cause of death nearly always was asphyxiation due to obstruction of the upper airways. Nowadays, patients rarely die of the disease. Particularly at risk are patients in whom the diagnosis hereditary angioedema due to C1-inhibitor deficiency has not been established.
HAE
due to C1-INH deficiency is inherited as an autosomal dominant
trait. Each patient is heterozygous for the C1-INH defect and has
one normal and one defective gene. Patients with HAE type I have
a normally expressed C1-INH gene and an abnormal or deleted gene
that is not expressed.
Patients
with HAE type II also have one normal gene. The other gene is
abnormal and is expressed but gives rise to the synthesis of a
dysfunctional C1-INH. The gene coding the C1-INH is located on
the long arm of chromosome 11. As a result of new techniques for
the identification of mutations, numerous mutants have become
known; until now more than 100. HAE type II is brought about by
point mutations in the C1-INH gene.
C1-INH
controls the spontaneous auto-activation of the first complement
component (C1). A functional C1-INH deficiency gives rise to
complement activation and recurrent angioedema. In 1963 Donaldson
and Evans identified C1-INH deficiency as the cause of HAE. C1-INH
is a glycoprotein with a molecular weight of 105,000 daltons. It
is a single-chain protein, which consists of 478 amino acids and
is synthesized mainly in hepatocytes, and to a lesser extent also
in blood monocytes, skin fibroblasts and endothelial cells of the
umbilical cord. As a result of activation of the initial phase of
the complement system, there is a permanent reduction of C2 and C4
in plasma. The exact pathogenesis of angioedema has not yet been
clarified and in particular the main mediator which brings about
an increase in vascular permeability is not known. It has been
postulated that the edema is caused by increased amounts of
bradykinin formed via kallikrein not adequately inhibited by C1-INH.
A second hypothesis suggests that the cleaved C2 is responsible
for the development of increased permeability of the vessel walls.
Laboratory
diagnosis should include the following parameters if there is
clinical evidence to suspect that a patient suffers from HAE:
In
healthy subjects, the plasma concentration of C1-INH lies between
15 and 35 mg/dl. In 85% of patients with HAE there is a
quantitative C1-INH deficiency in plasma, which is also
detectable in the intervals between attacks
Therapeutic efforts for HAE are aimed at the treatment of an acute attack as well as long-term and short-term prophylaxis.
Acute treatment is absolutely indicated in life-threatening episodes such as swellings of the mucous membranes of the mouth, pharynx and larynx. The injection of C1-INH concentrate (Berinert P, Aventis Behring, Liederbach, Germany) can be life-saving. If this is not available, infusions of fresh frozen plasma (FFP) may also have a favorable effect. The risk of transmission of viruses or other infectious agents must be borne in mind with both forms of treatment. Patients with laryngeal edema constitute an emergency because of the danger of asphyxiation and should be treated in hospital immediately. The further treatment of acute life-threatening laryngeal edema due to hereditatry angioedema depends on the extent of glottal or laryngeal edema. If the patient has life-threatening dyspnea, intubation should be carried out immediately, also using fiber optics; in the event of an extreme emergency a tracheotomy or cricothyrotomy might become necessary.
Attenuated androgens such as danazol or stanozolol may successfully be used for long-term prophylaxis. Because of a number of side effects such as virilization and liver diseases including impairment of liver function and adenoma of the liver, this kind of treatment is not appropriate for all patients, and those who are treated have to be monitored carefully. In addition, epsilon-aminocaproic acid and tranexamic acid have proved to be effective, although not in all patients. In severe cases of the disease, long-term treatment with C1-INH concentrate can be carried out, but the risk of transmission of infectious agents must be borne in mind.
Short-term
prophylaxis should be carried out particularly before oral and
dental surgery and tonsillectomy but also before other forms of
surgical intervention in the region of the head or after trauma
to the head. C1-inhibitor concentrate (Berinert P) can be used
for short-term prophylaxis. If this is not available, short-term
prophylaxis is also possible with danazol.
