Angioedema

Outline
• Angioedema
• Classification
• Clinical presentation
• C1 inhibitor
• Hereditary Angioedema
• Acquired Angioedema
• Idiopathic Angioedema

Angioedema
• Localized, transient, episodic edema of the
deeper layers of the dermis and subcutaneuous
tissue or of the mucosa of the GI tract,
respiratory tract
• Result of interstitial edema from mediators
affecting capillary and venule permeability
• Caused by extravasation of plasma in the
affected areas, which at times is accompanied
by nonspecific, minimal cellular infiltrate

Frigas and Nzeako: Clinical Reviews in Allergy and Immunology

Episodes of angioedema may be classified
in two broad categories:
• Acute angioedema (single episode)
• Acute recurrent angioedema (three or
more episodes of angioedema within a 3-6
month period)


Classification


Major caused of urticaria and
angioedema
1. Drug reactions
2. Food or food additives
3. Inhalation, ingestion of, or contact with
Ag
4. Transfusion reaction
5. Infection : bacterial, fungal, viral, and
helminthic

Allen P. Kaplan : Middleton’s Allergy 7 edition

6. Insects (papular urticaria)
7. Collagen vascular diseases
8. Malignancy: angioedema with acquired
C1 and inactivator ( INH) depletion
9. Physical urticarias
10. Urticaria pigmentosa: systemic
mastocytosis


11. Hereditary diseases
1. Hereditary angioedema
2. Familial cold urticaria
3. C3b inactivator deficiency
4. Amyloidosis with deafness and urticaria
(Muckle-Wells syndrome)
12. Chronic autoimmune urticaria and
angioedema
13. Chronic idiopathic urticaria and
angioedema
14. Idiopathic angioedema

Kanokvalai Kulthanan et al: Clinical and Developmental Immunology 2007

Clinical presentation
• Angioedema of the skin is nonpitting, with
ill-defined margins
• Skin is swollen, tender, and warm
• Frequently a burning sensation is present,
but pruritus is typically uncommon (fewer
mast cell and sensory nerve ending)
• Attacks of angioedema may last a few
days and usually resolve spontaneously

• The time from onset of angioedema to
complete obstruction of the upper airway
may vary from minutes to 14 hr
• Intestinal obstruction may result from
angioedema of the wall of the GI tract
• Nausea, vomiting, and abdominal pain
may be severe at times, mimicking acute
abdomen, rarely diarrhea

• Fever and leukocytosis are unusual in
angioedema
• Cases of cerebral angioedema, leading to
migraine and transient ischemic attacks
have been described


C1 Inhibitor
• Complement regulatory protein
• C1 INH is an α2-globulin of 105 kDa and is
synthesized mainly by hepatocytes
• Major functions inhibition of autoactivation C1,
bind to C1r and C1s and dissociates the C1
complex (C1r2-C1s2-C1-INH2 complex)
• Inactivation of the coagulation factors XIIa, XIIf,
and XIa, direct inhibition of activated kallikrein

Kathleen E. Sullivan: Middleton’s Allergy 7 edition

Hereditary angioedema
(C1 INHIBITOR DEFICIENCY)
• 1 in 10,000 to 1 in 150,000
• Located in chromosome 11q13.1
• Heterozygous, AD but 20-25%
Spontaneous mutation
• Mildly increased susceptibility to infection
and increased risk of SLE ( chronic
consumption of C2, C4)
• Angioedema not associate with urticaria

• Hx
– Involvement airway in the absence of
anaphylaxis
– abdominal episodes
– a positive family history
– angioedema arising after trauma
• 5% of people who carry a C1 inhibitor
mutation are asymptomatic


• Half of patients have had episodes before
the age of 10 years
• Episodes may be as infrequent as 1/year
or as frequent as 1/month and the
frequency and the severity of episodes do
not correlate with laboratory features


• The extremities, face, or genitalia are most
often involved
• Involved GI – abdominal pain, vomitting,
rarely diarrhea
• 1/3 of patients with C1 inhibitor deficiency
had undergone an appendectomy or
exploratory laparotomy for abdominal pain


• Involved airway, upper respiratory tract
swelling leading to respiratory arrest
• Mortality rate high as 30–40%, is mostly a
result of obstruction of the upper airway
• Angioedema typically progresses for 1–2
days and resolves in another 2–3 days
• Common precipitants are illness, hormonal
fluctuations, trauma, and stress

• C1 inhibitor promoter is androgen responsive,
men have fewer problems in general than
female patients
• May also explain the common complaint that
symptoms vary with menstruation
• Mechanism underlying the angioedema is not
completely clear but relates to the role of C1
inhibitor as an inhibitor of both the classical
complement pathway activation and as an
inhibitor of the kinin pathway

•C1 inhibitor deficiency is
thought to lead to angioedema
through loss of inhibitory
activity for the intrinsic
coagulation pathway
•Factor XII (Hageman factor)
activation leads to the
activation of bradykinin, which
is one of the most potent
vasodilators known
•bradykinin leads to vascular
leak, and hence, angioedema
•cleavage product of C2b, C2-
kinin is produced by plasmin
•Plasmin is itself activated by
factor XII
•C2-kinin has some effect on
vasodilation
•activation of factor XII is often
due to vascular damage and
collagen expose

• Type I : is a concomitant decrease in
protein levels and function
• Type II :is associated with the production
normal but dysfunctional protein ( most
common 85%)
• Recommended that both antigenic and
functional levels
• Typical functional level is approximately
25–40% of normal in both types

• Ideally, the episodes of angioedema are
prevented
• Most common strategy for prevention is
the use of attenuated androgens
• In children, the use of androgens is
discouraged due to concerns about
closure of the epiphyses and tranexamic
acid is often used


• Short-term prophylaxis for dental
procedures, surgical procedures, or other
situations where significant trauma
• Attenuated androgens are typically used,
then FFP is usually given prior to the event
• Europe and Austaria, pasteurized C1
inhibitor concentrate is available for both
short-term prophylaxis and treatment and
is very effective


• Episodes also occur in children, pre-adolescent
girls and adolescent girls
• may be on an antifibrinolytic agent that is much
less effective than an attenuated androgen
• Acute episodes arise in the undiagnosed patient
or in non-compliant patients, corticosteroids,
epinephrine, and antihistamines have no effect
– Supportive care and close observation, pharyngeal
swelling can progress to airway compromise in a few
hours
– Narcotics are appropriate for abdominal pain


• C1 inhibitor concentrate is best option where
available
• Antifibrinolytics to reduce the severity and length
of the episode and attenuated androgens may
do the same (do not begin effect for 24 hr)
• FFP and aprotinin have been used for acute
episodes
• FFP is thought to provide active substrate to
enhance further edema and is not routinely used
and side effects with aprotinin have limited its
use


• Polycystic ovary syndrome (increased
luteinizing hormone and testosterone are
not seen, Ultrasounds demonstrate
polycystic ovaries and Menstrual
irregularities ) is seen in approximately
one-third of female patients with C1
inhibitor deficiency
• attenuated androgen therapy improves the
polycystic ovaries


• Pregnancy poses a particular risk to both
the mother and the fetus
• Hormonal shifts of pregnancy lead to an
increased risk of angioedema
• Delivery is itself traumatic and an affected
mother has a 50% chance of transmitting
the disorder to her offspring


• Europe, C1 inhibitor is given
prophylactically
• USA, low-dose androgens (risks of
androgenization of the baby)
• FFP could be administered
prophylactically; however, there are no
data on this strategy


Acquired C1 INH deficiency
• Nonhereditary angioedema characterized
by normal C1-INH
• Age of onset is after 30 years
• Caldwell and colleagues described the first
patient in 1972
• Mostly associated with lymphoproliferative
disorders

Lorenza Chiara Zingale: Immunol Allergy Clin N Am

C1-INH or the classic complement pathway
was consumed by the neoplastic lymphatic
tissues

Autoimmune mechanism

• 1986, Jackson and colleagues, discovered
an autoreactive immunoglobulin G against
C1-INH
• Autoimmune mechanism could be the
cause of acquired C1-INH deficiency
• Because the first patients who had
autoantibodies to C1-INH looked
otherwise healthy

• 1985, Geha and colleagues, mechanism of
complement consumption
• Paraproteins had immunoglobulins against the
idiotypic determinants of the M components
• Idiotype–anti-idiotype immune complexes fixed
C1q and consumed C1-INH
• Direct proof in vivo increased consumption of
C1-INH was provided in 1986 by Melamed and
colleagues (injected patients with radiolabeled
C1-INH and C1q)

Acquired C1-INH deficiency was divided into
two separate forms
– type I, paraneoplastic, mainly associated
with lymphatic malignancies or other
diseases
– type II, autoimmune, caused by
autoantibodies to C1-INH

• Only 14% of patients with acquired C1 inhibitor
deficiency had no associated medical condition
• Lymphoproliferative diseases and acquired C1-
inhibitor deficiencies
• Many from B cell lymphoproliferative diseases
that ranged from monoclonal gammopathies of
undetermined significance (MGUS) to true
malignancies (NHL)
• NHL is markedly increased in patients who have
angioedema and acquired C1-INH deficiency

• Variant rarely occurs in association with
malignancies of the rectum, stomach, and
breast; rheumatoid arthritis and systemic
lupus erythematosus; Churg-Strauss
vasculitis; lupus anticoagulant; erythrocyte
sensitization; livedo reticularis; and
infections with human immunodeficiency
virus, hepatitis C and B viruses,
Echinococcus granulosus, and
Helicobacter pylori

• The differences between the two forms are
absence of family history, late onset of
symptoms (after the fourth decade of life), and
response to treatment
• C1-INH function and antigen, C4 and C1q
markedly reduced (usually far below 50% of
normal), with a normal C3
• C1-INH antigen can be normal, when elevated
amounts of cleaved inactive C1-INH circulate in
plasma

• Autoantibodies to C1-INH may be
detected as immunoglobulins preventing
C1-INH function or binding C1-INH
• Alsenz and colleagues developed a solid-
phase ELISA for detectin immunoglobulins
binding to C1-INH coated to microtiter
plates (simple and highly sensitivity)

• Course of and prognosis for angioedema
with acquired C1-INH deficiency depend
on the underlying disease and the
availability of proper therapy for life-
threatening angioedema
• Angioedema attacks usually resolve
without treatment, patients are exposed to
the risk for laryngeal edema

• Successful treatment of the underlying
disease has been shown to resolve
angioedema symptoms
• immunosuppressive regimens
(cyclophosphamide, with or without
steroids) have been used for suppressing
the formation of anti–C1-INH
autoantibodies in isolated patients who
had acquired C1-INH deficiency

• For long-term prevention of angioedema
recurrences, patients are treated with
attenuated androgens and antifibrinolytic
agents
• Acquired C1-INH deficiency are often
resistant to attenuated androgens but
better response to antifibrinolytic agents

Treatment Adult Pediatric Comments
Tranexamic acid 1–3g/day p.o. as 25–50mg/kg b.i.d.– Not available in the
(Cyklokapron divided doses for t.i.d. as prophylaxis, USA
prophylaxis, 1g p.o. 1.5g/day for acute
q. 3–4h until episode episodes (available
resolves for acute as i.v. form)
episodes
Epsilon 1g p.o. t.i.d. as 100mg/kg q.4–6h The only
aminocaproic acid prophylaxis, 1g/h as not to exceed antifibrinolytic
(Amicar) i.v. therapy for acute 30g/day as therapy. available in the
attacks Oral syrup available USA, has modest
for prophylaxis but efficacy. Cannot be
established: 6g/day used in neonates.
for children Oral dosing has
<11years and significant GI side
12g/day for children effects
>11years has been
used successfully


Danazol (Danocrine) 200mg p.o. q.d. as a 50–200mg p.o. q.d. Concern about
starting point for as a starting point androgenization and
prophylaxis (titrate for prophylaxis premature closure of
to effect), 400– (titrate to effect) and the epiphyses limits
600mg p.o. q.d. for consider q.o.d. or q. the use of
acute episode or 3 days in pre- attenuated
short-term adolescent children; androgens in
prophylaxis can use up to children. Titration to
400mg p.o. q.d.as desired effect is
short-term recommended
prophylaxis rather than to
laboratory criteria
Oxandrolone 2.5–20mg p.o. t.i.d. 0.1mg/kg per day as Has less
(Oxandrin) as prophylaxis prophylaxis. Not androgenizing
(titrate to effect). Not proven as short- effects than Danazol
proven as short- term prophylaxis or
term prophylaxis or treatment in a formal
treatment clinical trial


Bruce L:Immunol Allergy Clin N Am

Fresh frozen plasma 1000U as treatment 10–30U/kg as Very rapid effect,
(FFP) treatment (up to especially useful in
500–1000U total pregnancy

C1 inhibitor 1000U as treatment 10–30U/kg as Very rapid effect,
concentrate treatment (up to especially useful in
500–1000U total) pregnancy

Icatibant Bradykinin receptor
antagonist; awaiting
trial results

DX-88 Kallikrein inhibitor,
has shown efficacy
in early trials; could
be available later in
2007


• ACE inhibitors, estrogen replacement
therapy, and oral contraceptives should be
avoided in patients with either HAE or AAE

Idiopathic recurrent Angioedema
• Three or more episodes of angioedema
have occurred within a period of 6 months
to 1 year without any cause being
identified
• Diagnosis is made after a comprehensive
evaluation has ruled out the known causes
of angioedema

Evangelo Frigas:Immunol Allergy Clin N Am

• Women are affected slightly more often
than men, and at presentation 50% of
patients are found to have both urticaria
and angioedema
• Angioedema alone in chonic urticaria and
angioedema, 20%


• Excessive production or decreased
catabolization of molecules that increase
vascular permeability
• Histamine, tryptase, prostaglandin F2α
from mast cells, and bradykinin from
inappropriate and excessive activation of
the complement and kallikrein systems


• Food allergens (especially shellfish, nuts, and
peanuts), latex, and insect venoms as well as
several medications can release histamine from
sensitized mast cells and may produce
angioedema on an IgE-mediated basis
• Some medications (narcotics, polymyxin, d-
tubocurarine) may cause angioedema owing to
their ability to cause direct mast cell
degranulation in the absence of IgE antibodies
against the drug

• Pathogenesis of idiopathic recurrent
angioedema with or without urticaria is not
known

• Initial work-up includes the following
laboratory tests: complement C4, C1q,
CH50, C1 esterase inhibitor by functional
and quantitative assays, and a panel for
mast cell-mediator screening, which
includes measurements of tryptase and
calcitonin in the serum and histamine, N-
methylhistamine, and prostaglandin F2α in
a 24-hour urine collection.

• CBC, chemistry group, serum protein
electrophoresis, total serum IgE, ESR, and
a thyroid cascade, which includes testing
for antithyroid antibodies
• Allergy skin tests or specific IgE blood
tests are performed to rule out latex and
food allergy

• Devided into “histaminergic” and “non-
histaminergic” depend on response or lack
respons to antihistamine
• Isolated elevation of prostaglandin F2α in
the urine but normal levels of the other
mediators, patients may benefit from
treatment with aspirin

• step 1, we usually start with a nonsedating
or less-sedating antihistamine, such as
fexofenadine, cetirizine, loratadine, or
desloratadine, taken during the daytime
• step 2 by adding a sedating antihistamine
such as doxepin, hydroxyzine, or
diphenhydramine, usually taken at
bedtime
• step 3, cyclosporine, nifedipine,
methotrexate, androgens, warfarin

• treatment trials for 2 to 4 months with
either colchicine 0.6 mg once or twice
daily or dapsone 25 mg twice daily and
titrated up to 100 mg twice daily, or
sulfasalazine 500 mg once or twice daily
• recombinant interferon α, ASA
• Systemic glucocorticoids, although very
effective for the majority of patients with
recurrent angioedema

• prednisone 20 mg for 5 to 7 days usually
without tapering
• Omalizumab (case report 3 case hige IgE)

Summery
• Classification Angioedema
• C1 INH
• HAE
• AAE
• Idiopathic angioedema
• Treatmeant

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