| Hereditary angioedema (HAE) and acquired C1-inhibitor
deficiency are uncommon complement deficiencies which are caused
by the deficiency of a plasma protein known as C1-inhibitor.
They can lead to attacks of abdominal pain and/or severe swelling
in the tissues. This booklet describes what it means to have
hereditary angioedema and outlines the medical facts behind
both conditions.
Ann Price recalls her family's experience of hereditary angioedema
over four generations:
The story of hereditary angioedema in our family is a very
positive one. Although it started with much ignorance, fear,
pain and mismanagement, we now understand the disorder and
have confidence and enough control over the situation to live
full and active lives. We hope that in the future, with the
advances in gene therapy, the prospects will be still brighter.
I have told our story to encourage those who have had to struggle
- and perhaps continue to struggle - with many years of misdiagnosis
and inadequate treatment.
Let me start by introducing our family as we are today. I
am a 52-year-old part-time nurse. My husband John, also 52,
is a health and safety specialist. We have three children:
Helen, who is 24 and has just qualified as a doctor, David
who is 23 and studying medicine, and Edward, aged 13.
My own symptoms first occurred when I started taking the
contraceptive pill at the age of 23. I immediately experienced
severe bouts of gross oedema about once a week, involving
arms, legs, face and gut. It was very frightening. Only at
this stage was I told the family history of this weird condition.
My grandfather had HAE severely over many years and he died
at the age of 39. My father suffered severely until he was
30, when his symptoms suddenly ceased, never to return. Several
aunts and uncles were affected. My mother regarded the condition
as "all down to nerves" and "peculiar and all
in the mind". My doctor prescribed massive doses of antihistamines,
to no effect.
My symptoms continued, but gradually decreased over the next
few years. Doctors were emphatic that there was no connection
with the pill, but when I discontinued it the oedema stopped
completely.
When I became pregnant with my first child, Helen, I had
regular oedema from four months, but all symptoms ceased after
her birth. The same pattern occurred during my second and
third pregnancies, although the symptoms were more severe.
However, between the pregnancies I was free of symptoms.
Our third son, Andrew, appeared to be a very bonny, healthy
baby, but our lives were devastated when he tragically died
in infancy.
It was at this time that my GP spent an afternoon researching
into HAE at the postgraduate medical library on our behalf.
Subsequent blood tests revealed that Helen and David were,
like me, deficient in a susbtance in our blood called C1-inhibitor
(C1INH). However, they were symptom-free at the time. Because
of these diagnoses I was determined to find some answers.
As a nurse I had access to medical literature and our GPs
were supremely helpful. We found a specialist consultant in
London. Gradually over the next few years more information
and treatment became available.
Two years after Andrew, we had Edward, who also has HAE.
In l983 C1INH was being produced in Holland and towards the
end of my pregnancy with Edward I was the first patient in
this country to have C1INH injections. It was like a miracle.
What had been a three-day session of very acute abdominal
pain, vomiting and diarrhoea was relieved within an hour of
the injection.
The availability of C1INH has been the central factor in
transforming the lives of our family.
Without treatment, for instance, Helen would not have been
able to manage a career and she would have experienced a lot
of severe pain and distress. Her symptoms had increased in
severity since the age of 14. She suffered severe incapacitating
abdominal symptoms for three days out of every seven to ten
days. At first she was given high doses of Danazol, but the
androgenic properties of this were prohibitive. Her periods
became very erratic, her appetite and weight increased, she
developed facial hair and her voice deepened considerably.
She is now controlled by self-injecting two vials of ClINH
intravenously as soon as abdominal or throat symptoms develop.
Thanks to this replacement therapy Helen has been able to
qualify as a doctor. She now lives a normal and happy life
and has travelled all over the world.
David developed problems in adolescence, but his condition
appears to be less marked and he is maintained relatively
symptom-free on small daily doses of Danazol. He always keeps
C1INH available in case of severe symptoms or laryngeal emergencies.
Edward has the deficiency but is at present without symptoms.
However, we always have our safety net, in the form of C1INH,
at the ready.
The main points of our management at present are:
- Maintaining a sensible, positive attitude to HAE
- Making available letters and leaflets explaining HAE
- Wearing "Medicalert" bracelets
- Taking C1INH injections before any medical or dental treatment
- Taking Danazol for preventative therapy
- Always having available C1INH in case of emergencies
Because of the small risk attached to blood products we still
look forward to the day when gene therapy will provide an
actual cure for our condition.
Our Medical Advisory Panel explains the causes and treatment
of these two conditions.
Hereditary Angioedema
HAE occurs in approximately one in every 50,000 to 100,000
of the population. Although it is an inherited disorder, and
therefore present at birth, many people do not experience
symptoms until they are in their late teens or, occasionally,
much later in life.
HAE has an autosomal dominant pattern of inheritance. This
means that if one parent is affected, half of the children
will inherit the abnormal gene. However, in a significant
number of cases, the deficiency occurs spontaneously in individuals
without a family history. In these cases, it is thought to
be due to a new mutation in the C1-inhibitor gene in one of
the parents.
Acquired C1-Inhibitor Deficiency
Acquired C1-inhibitor deficiency is a recently described
form of the deficiency, and is also very rare. It is not inherited
but is caused when the body produces an antibody to its own
C1-inhibitor, which prevents C1-inhibitor from performing
its normal function (hence the alternative name for this condition:
autoimmune C1-inhibitor deficiency).
C1-Inhibitor, and the Effects of Its Deficiency
In healthy people C1-inhibitor acts as a brake on the
activity of the complement and kallikrein systems, which are
responsible for the swelling occurring at the site of an injury
to the body. In people who are deficient in C1-inhibitor,
the triggering of these systems is uncontrolled and leads
to leakage of fluid into tissues, causing excessive swelling.
This swelling can be quite gross and may affect any part of
the body. Swelling in the bowel can cause severe abdominal
pain; a swelling in the throat can interfere with breathing,
and therefore can have fatal consequences. A deficiency in
C1-inhibitor is, therefore, a potentially lethal condition.
Untreated, an attack of angioedema will usually last for
48 hours before abating.
As with other primary immunodeficiencies, there is currently
no known cure for either hereditary angioedema and acquired
Cl-inhibitor deficiency. Fortunately, modern treatment has
greatly improved the prospects and quality of life for people
with hereditary angioedema. Five main strategies are adopted:
- Avoidance of precipitating factors
- Prevention of acute attacks
- Treatment of acute attacks
- Maintenance therapy using drugs
- Maintenance therapy using inhibitor concentrate
Avoidance of precipitating factors
Attacks may be caused by a number of different events,
including mild trauma (such as dental treatment) and infections.
Oral contraceptives can worsen the disease in some women.
Prevention of acute attacks
If a person with HAE or acquired C1-inhibitor deficiency
requires surgical procedures (including dental manipulations),
action should be taken to prevent a possible attack. The person
should be admitted overnight prior to surgery and should receive
an infusion of concentrate. In addition, they should be monitored
carefully for 24 hours after surgery.
Treatment of acute attacks
Acute attacks are treated by general supportive measures
and also by infusion with the missing protein. Although this
blood product (C1-inhibitor concentrate) is commercially available,
it is not yet licensed, so it is not straightforward to obtain.
Usually, an infusion of 25 units per kilogram of body weight
will terminate an attack. Following infusion of the concentrate,
an attack should begin to remit within an hour. This can be
life-saving in the case of an attack which involves the head
or neck area.
If C1-inhibitor concentrate is unavailable, an acute attack
may be treated with fresh frozen plasma, which is more readily
available. However, the plasma contains complement components
which could theoretically make the condition worse, although
in practice this does not lead to problems.
If an attack of angioedema affects the throat, lips or mouth,
the person should go to hospital immediately. It is also unwise
to assume that all attacks of abdominal pain in patients with
C1-inhibitor deficiency are necessarily due to angioedema.
However, if symptoms are atypical and/or do not respond to
therapy, the person should go to hospital immediately.
In order to save time and to help the casualty officer, a
person with C1-inhibitor deficiency should carry a card or
a letter from their immunologist stating the nature of the
disease, the recommended treatment and the telephone number
at which the immunologist can be contacted.
Maintenance therapy using drugs
The frequency and severity of the long-term attacks of
angioedema can be reduced by androgenic steroids, such as
Danazol or Stanozolol, and by tranexamic acid. Both types
of drug may produce side effects, but in most patients these
can be kept to a minimum if advice is available from an experienced
physician, and if the drug is given at the lowest effective
dose.
Maintenance therapy using inhibitor concentrate
It is possible to use inhibitor concentrate in maintenance
therapy. Although this would seem to be preferable to drug
therapy, the concentrate has the disadvantage of lasting only
for a short time in the body. It is therefore inappropriate,
except for the management of particular procedures such as
dental extractions. Every effort must be made to manage the
condition using the drugs mentioned above. Only when this
approach fails, or if the drugs are contraindicated, should
reliance on the inhibitor be considered. This is unusual so
experience so far with the inhibitor is scant.
The importance of support
The value of a support group like the PiA for people with
hereditary angioedema and acquired C1-inhibitor deficiency
is enormous. Because the conditions are rare and treatment
is expensive, people feel themselves to be in a very vulnerable
situation, especially in the current climate of change in
the health service. The PiA aims to keep people informed,
to enable contact with others and to give advice on specific
non-medical issues when appropriate. In particular, we strongly
recommend that each person is looked after by a physician
experienced in the management of these rare conditions.
Medical information published by the PiA
is approved by our Medical Advisory Panel. However, it is
intended for general guidance only, and should not be used
in place of the personal consultation needed with your physician.
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