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Hereditary Angioneurotic Edema: Review of the Literature

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Hereditary Angioneurotic Edema: Review of the Literature

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Congenital C1-inhibitor deficiency, or hereditary angioneurotic edema (HAE), is a rare autosomal dominant disease due to alterations in the C1 inhibitor gene that results in a deficiency of antigenic and/or functional C1-INH. Affected patients are heterozygous, and their deficiency is incomplete, many of them having up to 20% of the normal amount of the inhibitor. The disease is characterised by recurrent, circumscribed, non-pitting, and non-pruritic subepithelial swellings of sudden onset, which fade during the course of 48-72 hours, but can persist up to 1 week. Lesions can be solitary or multiple and primarily involve the extremities, larynx, face, and bowel wall. Bradykinin is believed to be the main, but certainly not the sole, mediator responsible for the bouts of edema in HAE. The diagnosis is suggested by family history, the lack of accompanying pruritus or urticaria, the presence of recurrent gastrointestinal attacks of colics, and episodes of laryngeal edema. Diminished C4 concentrations during symptomatic periods are highly suggestive for the diagnosis. Further laboratory diagnosis depends on demonstrating a deficiency of C1-INH antigen (type I) in most kindreds, but some kindreds have an antigenically intact but dysfunctional protein (type II) and require a functional assay to establish the diagnosis. Prophylactic administration of either attenuated androgens or protease inhibitors has proved useful in reducing frequency or severity of attacks. Infusions of a vapour-heated C1-INH concentrate are safe and effective means of both preventing and treating attacks. Nevertheless, this treatment is expensive and this extract is not readily available. It is emphasised that administration of angiotensin converting enzyme inhibitors is contraindicated in patients suffering from protease inhibitor deficiency states.
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22 HEREDITARY ANGIONEUROTIC EDEMA: REVIEW OF THE LITERATURE
Acta Clinica Belgica, 2000; 55-1
HEREDITARY ANGIONEUROTIC EDEMA:
REVIEW OF THE LITERATURE
D.G. Ebo
1
, W.J. Stevens
1
ABSTRACT
Congenital C1-inhibitor deficiency, or hereditary
angioneurotic edema (HAE), is a rare autosomal dom-
inant disease due to alterations in the C1 inhibitor gene
that results in a deficiency of antigenic and/or functional
C1-INH. Affected patients are heterozygous, and their
deficiency is incomplete, many of them having up to 20%
of the normal amount of the inhibitor. The disease is
characterised by recurrent, circumscribed, non-pitting,
and non-pruritic subepithelial swellings of sudden onset,
which fade during the course of 48-72 hours, but can
persist up to 1 week. Lesions can be solitary or multiple
and primarily involve the extremities, larynx, face, and
bowel wall. Bradykinin is believed to be the main, but
certainly not the sole, mediator responsible for the bouts
of edema in HAE. The diagnosis is suggested by family
history, the lack of accompanying pruritus or urticaria,
the presence of recurrent gastrointestinal attacks of col-
ics, and episodes of laryngeal edema. Diminished C4
concentrations during symptomatic periods are highly
suggestive for the diagnosis. Further laboratory diag-
nosis depends on demonstrating a deficiency of C1-INH
antigen (type I) in most kindreds, but some kindreds
have an antigenically intact but dysfunctional protein
(type II) and require a functional assay to establish the
diagnosis. Prophylactic administration of either attenu-
ated androgens or protease inhibitors has proved useful
in reducing frequency or severity of attacks. Infusions
of a vapour-heated C1-INH concentrate are safe and
effective means of both preventing and treating attacks.
Nevertheless, this treatment is expensive and this extract
is not readily available. It is emphasised that adminis-
tration of angiotensin converting enzyme inhibitors is
contraindicated in patients suffering from protease
inhibitor deficiency states.
KEY-WORDS AND ABBREVIATIONS
Angiotensin-converting enzyme (ACE), ACE-inhi-
bitor (ACEI), bradykinin, C1-esterase inhibitor (C1-INH),
epsilon-aminocaproic acid (EACA), hereditary angioneu-
rotic edema (HAE), kininase, protease inhibitor
PATHOPHYSIOLOGY
The biochemical alteration of HAE, i.e. a decreased
level of C1-INH, was discovered by Donaldson et al. (1).
C1-INH, a α
2
-neuraminoglycoprotein of 105 kDa, is
synthesised primarily by hepatocytes and monocytes
and is present in a normal serum concentration of
approximately 30 mg/dL. As a member of the “super-
family” of the serpine protease inhibitors, its spectrum
of inhibitory activity, is defined by a 444 arginine – 445
threonine dipeptide at the reactive centre. The target
proteins of C1-INH include the proteases C1r and C1s
(complement system), factor XIIa and kallikrein (con-
tact system), factors XIa, XIIa, and XIIf (coagulation
cascade), and plasmin (fibrinolysis) (2-4). All these 4
protease systems are at various extents activated during
bouts of angioedema in HAE that occur when the serum
C1-INH concentration drops below the crucial thresh-
old of approximately 30% of the normal value (2, 5-7)
(Figure 1). There has been controversy about the media-
tor(s) responsible for the increased vascular permeability
causing the bouts of angioedema in HAE. During
attacks, patients with HAE have been demonstrated to
have increased urinary histamine levels (8). Histamine
is not considered to be pivotal in the pathogenesis of the
angioedema because the patients do not experience pru-
ritus, and antihistamines neither prevent nor ameliorate
the angioedema. The source of histamine is probably
the mast cell that is activated by the anaphylatoxins C3a
1
Department of Immunology, Allergology and Rheumatology,
University of Antwerp (UIA), Belgium.
Correspondence to: Dr. D. Ebo, Department of Immunology,
Allergology and Rheumatology, University of Antwerp (UIA), Bel-
gium. Universiteitsplein 1, B 2610 Antwerpen, Tel: 32-3-820.25.95,
Fax: 32-3-820.26.55, E-mail: immuno
@
uia.ua.ac.be
HEREDITARY ANGIONEUROTIC EDEMA: REVIEW OF THE LITERATURE 23
Acta Clinica Belgica, 2000; 55-1
and C5a that are generated as a consequence of the
unbridled activation of the complement cascade. In con-
trast, there is clear evidence that an important mediator
belongs to the kinin family. Fields and colleagues (9)
first provided evidence of the involvement of bradykinin
in HAE. Bradykinin, a nonapeptide cleaved from the
inactive precursor high-molecular-weight kininogen by
plasma and tissue kallikrein (10), is a highly potent acti-
vator of the L-arginine nitric oxide system (i.e., EDRF,
endothelium-derived relaxing factor). Bradykinin causes
vasodilatation, increases vascular permeability, and also
produces hypotension when injected intravenously in
humans (11). In fact, bradykinin was observed to be
tenfold more potent than histamine in producing vasodi-
latation (12). Subsequently, activation of prekallikrein
and consumption of high-molecular-weight kininogen
during attacks of angioedema was observed (13).
Recently, substantial rises in plasma bradykinin have
been demonstrated during acute attacks of hereditary,
acquired, or captopril-induced angioedema (14). Accu-
mulation of bradykinin seems thus also to be responsi-
ble for the angioedema that occurs in angioedema due
to angiotensin-converting enzyme inhibitors (15, 16).
Since the 4 C1-INH-controlled protease systems release
different vasoactive peptides upon cleavage of their
components, it seems unlikely that symptoms in HAE
are solely due to bradykinin. Other candidate mediators
are a kinin-like peptide released from C2 during com-
plement activation (2, 7, 17, 18) and thrombin, the final
enzyme of the coagulation system (6, 7). The relevance
of the activation of the contact and tissue factor coag-
ulation pathways for edema formation and generation
of thrombosis, however, remain to be assessed. Only a
few acute thromboembolic processes have been report-
ed occurring during an episode of angioedema in HAE.
The paucity of the data prevents us to formulate any
conclusion, however, it urges for careful and long-term
surveillance of patient with HAE (7, 19).
GENETICS
HAE is the most common form of angioedema due to
a genetic defect, and it is the most common disease relat-
ed to a complement protein deficiency. The prevalence
Figure 1 — Pathophysiology of angioedema due to C1-INH deficiency.
24 HEREDITARY ANGIONEUROTIC EDEMA: REVIEW OF THE LITERATURE
Acta Clinica Belgica, 2000; 55-1
of HAE is estimated at 1/50.000, with no reported bias
in different ethnic groups. Several studies indicate that
up to a quarter of these alterations are found in patients
without a family history of HAE and represent de novo
mutations (20, 21). The molecular basis of such a high
rate of de novo mutations remains presently unknown.
The original description of HAE is attributed to Osler (22)
who clearly recognised its hereditary nature. Approxi-
mately 30 years later, the disease was reported to show
an autosomal dominant mode of transmission (23).
A single gene on chromosome 11 (p11.2-q13) encodes
C1-INH. No other serpin is known to be encoded on
this chromosome: the α
1
-antitrypsin gene is on chro-
mosome 14 (q32.1), as is that for α
1
-antichymotrypsin,
while the locus for anti-thrombin III is on chromosome
1 (q23-25). The defect in HAE is highly heterogeneous
and two phenotypic variants were originally described
(24). In HAE type I the molecular defects are distrib-
uted over all exons and exon/intron boundaries and
include Alu-repeat-mediated deletions or duplications,
missense mutations, frameshifts, stop codon mutations,
promoter variants, splice site mutations and deletions of
a few aminoacids (21, 25, 26). However, single base
changes have also been demonstrated to cause type I
HAE (20, 26). These substitutions often affect the intra-
cellular transport of C1-INH protein and result in
significant reduction or absolute impairment of protein
secretion. An interesting promoter variant was found in
an exceptional family with recessive transmission of low
C1-INH levels and angioedema (21). Point mutations
and micro-deletions or -insertions are scattered along
the entire C1-INH gene. Generally, mutations within the
reactive centre loop residues impair the critical recog-
nition of the inhibitor by the protease. Mutations, other
than in the reactive centre loop, are likely to interfere
with specific serpin structural rearrangements. These
folding abnormalities may even result in conversion of
the inhibitor to a substrate (20, 26). Mutations that result
in over-insertion of the reactive centre loop promote
polymerisation of the protein whose secretion is
impaired, and, give birth to a biochemical phenotype
intermediate between the typically quantitative defect and
that of the qualitative defect (27). Because the secretion
of the mutant protein remains unimpaired and its ina-
bility to complex with proteases increases its plasma
half-life, generally, in HAE type II, high plasma levels
of a dysfunctional protein are observed. Since patients
with HAE are heterozygous, theoretically, the serum
level of C1-INH should average 50% of normal. Instead,
the mean serum level of C1-INH in HAE is less than
30% of the normal values. Biochemical evidence for
interference between particular mutant proteins and the
intracellular transport and/or catabolism of the intact
C1-INH protein has emerged (28, 29). However, strong
consumption of circulating C1-INH protein remains the
most likely explanation for the observation that the func-
tional C1-INH level is approximately 15 to 25% of the
normal value (30).
In contrast to HAE, the C1-INH genes are unaffect-
ed in patients suffering from either type of acquired
angioneurotic edema (AAE), as is C1-INH gene tran-
scription and translation, and C1-INH secretion. AAE
type I is biochemically distinguishable from AAE type
II by a significantly decreased concentration of C1-INH
antigenic level. In AAE type I, C1-INH is catabolised
more rapidly, due to the presence of immunoglobulin-
antiidiotype complexes associated with lymphoprolif-
erative diseases that massively activate C1, leading
to direct consumption of C1q,r,s, and subsequent
consumption of C1-INH. AAE type II is serologically
characterised by only a modest decrease of antigenic
C1-INH (60-70% of normal) but a marked reduction in
functional C1-INH. The pathogenesis of AAE type II is
the presence of circulating C1-INH-specific autoanti-
bodies. The clinical manifestations and complement
profiles of AAE are similar to those of HAE, except the
low level of C1 complex (measured as C1q) that char-
acterises AAE. In AAE, effectiveness of treatment is im-
paired by the rate of C1-INH catabolism (2, 4, 7, 20, 31).
CLINICAL MANIFESTATIONS
HAE is characterised by attacks of circumscribed,
non-pitting, and non-pruritic subepithelial angioedema
of sudden onset, which develop fully within a few hours
and fade during the course of 48-72 hours, but can
persist up to 1 week. All clinical characteristics are iden-
tical in both sexes, as well as in different phenotypes
and genetic variants. The frequency of the attacks varies
considerably from less than one to over 25 per year
(20, 32, 33), and some patients are asymptomatic. Lesions
can be solitary or multiple and primarily involve the
extremities, larynx, face, and bowel wall. Angioedema
is frequently recurrent and the severity is variable and
may fluctuate. Generally it resolves without harm, how-
ever, laryngeal or tracheal angioedema may result in
asphyxiation and remains the major cause of death
(1, 2, 4, 20, 22, 31-35). Before advent of therapy, mor-
tality was as high as 30% (20, 22, 34, 35). Abdominal
symptoms (colic pain, nausea, vomiting, watery diar-
rhoea, abdominal distension, and ascites) caused by
intestinal wall edema, at times severe, may be the sole
HEREDITARY ANGIONEUROTIC EDEMA: REVIEW OF THE LITERATURE 25
Acta Clinica Belgica, 2000; 55-1
clinical presentation of the disease (1, 22, 31-36). The
diarrhoea is caused by intraluminal fluid in the edematous
gut. Hypotension, tachycardia, hemoconcentration and
prerenal renal failure can result from intravascular vol-
ume depletion (34). Central nervous system symptoms
suggestive of focal cerebral edema, such as headaches,
hemiparesis, or seizures, may occur (1, 22, 33, 34).
Urticaria is not a feature of HAE, but attacks may be
associated with some erythema and an annular or ser-
pentine-like rash may herald attacks (20, 22, 34). It is
noteworthy that the bronchial tree is never involved in
attacks of HAE. In most patients the initial episode of
angioedema occurs around the age of 10. In a few
patients initial presentation occurred when they were over
50 years old (32-34) or, during the child’s first years
(7, 36). We recently observed a girl who presented with
severe HAE at the age of 2 years. Well-known precip-
itating events are mental and physical stress, minor
traumas, insect stings, food (e.g., alcohol), dental or sur-
gical procedures, intercurrent infection (e.g., tonsillitis)
and trivial activities (1, 20, 31-35). In about half of the
reported cases a precipitating event can not be identified
(20, 31). Menstruation, pregnancies, use of oral contra-
ceptives containing estrogens and postmenopausal
estrogen substitution seem to have major effect on HAE
activity (1, 20, 31-34). In contrast, progestational drugs
such as norgestrienone seem to have no effects on the
symptoms of HAE and may thus constitute a valuable
alternative (20, 33). Some authors observed a clear
increase of attacks during the menstrual periods, whilst,
after the menopause, generally the disease improves
(1, 33, 34). The effect of pregnancy on HAE appears to
be unpredictable, some reporting a benign course and
others an exacerbation. Episodes of abdominal pain and
edema should be carefully assessed and differentiated
from obstetric causes. The effect of HAE on the
outcome of pregnancy itself has not been established
(20, 32-34, 37, 38). Vaginal delivery does not seem to
require any specific precautions. Normally, angiotensin-
converting enzyme (identical to kininase II, peptidyl
dipeptide hydrolase), by releasing the carboxy terminal
dipeptide Phe-Arg, rapidly inactivates the nonapeptide
bradykinin, and converts angiotensin I to angiotensin II,
a potent vasoconstrictor. ACEIs reduce the function
of ACE, thereby producing a vasodilatory effect (39).
Because the pivotal role of bradykinin in C1-INH
deficiency related angioedema, in a letter, Shepherd (40)
was the first to express concern about the administration
of ACEIs to patients with C1-esterase inhibitor deficien-
cy. Two publications highlighted on the more frequent
and/or severe episodes of angioedema as a consequence
to the oral or intravenous administration of ACEIs in
such patients (41, 42). Patients suffering from bouts of
angioedema may also present other enzyme deficiencies.
For example, a familial deficiency of carboxypeptidase
N (i.e., kininase I), hereditary deficiency of α
1
-antit-
rypsin (Pi-ZZ phenotype) and partial deficiency of com-
plement C4, and to familial α
1
-antitrypsin deficiency
(Pi-MZ phenotype) (43-45). It seems reasonable to
anticipate that all these conditions might predispose to
an increased risk for ACEI-induced angioedema and,
therefore, should also be considered as contraindications
to the use of ACEIs. Because angiotensin II receptor
antagonists do not inhibit bradykinin degradation, they
have been advocated to constitute a valuable alternative
for ACEIs. However, angioedema did occur in some
patients treated with the angiotensin II receptor blocker
losartan (46, 47). With regard to the underlying mech-
anism of angioedema in patients with HAE it is
certainly worthwhile to mention the anaphylactoid reac-
tions observed during dialysis with AN69 membranes,
especially in combination with ACEIs (48). Here, the
excessive accumulation of bradykinin results as a
consequence of: a) contact activation of the intrinsic
coagulation pathway during the first minutes of
hemodialysis and b) reduced breakdown of bradykinin
by the ACE inhibition.
DIAGNOSIS
Because HAE is potentially life threatening but treat-
able, early diagnosis is mandatory. Measurement of the
serum C4 titre is an efficacious screening test. Normal
concentrations during symptomatic periods rule out the
diagnosis, whereas depressed levels warrant additional
evaluation. Further laboratory diagnosis depends on
demonstrating a deficiency of C1-INH antigen (type I)
in most kindreds (approximately 85%), but some
kindreds have an antigenically intact non-functional
protein (type II) and require a functional assay to estab-
lish the diagnosis (Table 1). The demonstration of low
C1q levels differentiates acquired C1-INH from the
genetic variety. The importance of establishing the
correct diagnosis cannot be overemphasised. It can avert
potentially fatal consequences, such as larynx obstruction
and unnecessary abdominal surgery and investigations
(20, 32, 33, 35).
TREATMENT
Three distinct phases in the management of HAE are
classically recognised: treatment of exacerbation, short-
26 HEREDITARY ANGIONEUROTIC EDEMA: REVIEW OF THE LITERATURE
Acta Clinica Belgica, 2000; 55-1
T
able 1 —
Biochemical complement profiles in angioedema.
(From Huston et al. (4), Sim et al. (31) and de Wazières et al. (33)
Disease C1-INH level Complement level
Antigenic Functional CH
50
C4 C1q C3 Para Protein Anti-C1 INH
Type I HAE ↓↓N* NN
Type II HAE N** N* NN
Type I AAE ↓↓N* ↓↓N* +
Type II AAE N* N* ↓↓N* +
HAE: hereditary angioneurotic edema; AAE: acquired angioneurotic edema
* Small decrease or
** increase may be seen
T
able 2 —
C1-INH deficiency: therapeutic management. (Adapted from Huston et al. (4).
Maintenance therapy
Agent Dose (/day) Mechanism Comments/adverse events (AE)
Attenuated androgens*
– Danazol 50 – 600mg Anabolic for Prophylaxis**:
Stanozolol 1 – 4mg C1-INH gene Danazol: 200 mg t.i.d. (5-10d )
Stanozolol: 1 mg q.i.d.
AE: hepatitis, virilisation
Anti-fibrinolytics
– Tranexamic acid 1 – 2g Inhibit F XII, C1 AE: thrombosis
ε-aminocaproic acid 6 – 10g and/or Plasminogen AE: thrombosis, myonecrosis
Acute attacks (treatment to be continued until angioedema resolves)
£
Vapour-heated C1-INH 500 – 2000U
$
Prophylaxis**:
concentrate* Passive replacement AE: virus transmission, allergic reaction (8)
Fresh frozen plasma 250 – 500mL Prophylaxis**: 2 to 4 x 250 mL
AE: virus transmission, transfusion reaction,
Tranexamic acid Up to 8g See above See above
* Treatment of choice
** short-term preventative management in case of surgery and/or invasive investigations
£
Epinephrine, corticosteroids, and antihistamines are commonly used but have no proven efficacy.
$
1 unit equals the amount of C1-INH contained in 1 mL of normal human plasma.
HEREDITARY ANGIONEUROTIC EDEMA: REVIEW OF THE LITERATURE 27
Acta Clinica Belgica, 2000; 55-1
term prophylaxis and maintenance therapy (Table 2).
For all types of C1-INH deficiency exacerbation of
angioedema is managed by supportive methods with
particular attention to the maintenance of a free airway.
Because, notwithstanding early and accurate treatment,
severe oropharyngeal angioedema may necessitate emer-
gency intubation and/or tracheostomy, such patients
should be monitored closely in a hospital setting until
the attack resolves. No evidence exists for efficacy of
epinephrine, H
1
and H
2
antihistamines, or corticosteroids
in treating an acute angioedema secondary to C1-INH
deficiency (1, 34). Nevertheless, it seems reasonable to
suggest these drugs for patients presenting with life-
threatening attacks. The treatment of choice for acute
attacks of HAE is replacement therapy with purified
vapour-heated C1-INH and has been reported safe and
well-tolerated (7, 20, 38, 49-51). Generally 1,000 to
2,000 U of C1-INH concentrate are sufficient to stop
severe attacks within 30-60 minutes. However, problems
can arise in AAE, especially in the presence of C1-INH
antibodies. These patients may need up to 10,000 U in
order to revert a severe attack. Because in most countries
there is no (commercial) source of C1-INH concentrate
readily available this usually may not be feasible. Infu-
sions of fresh frozen plasma have been administrated
successfully as treatment of severe attacks of HAE
(32, 52). Although the use of fresh frozen plasma for
the treatment of an ongoing attack is considered as a
double-edged sword: not only does it provide the defi-
cient protein but also substrates for further activation and
progression of angioedema, it is a valuable alternative
for C1-INH concentrate. Antifibrinolytic agents, i.e.,
tranexamic acid in dosages up to 8 g intravenously or
orally have also been shown to be beneficial, only when
the drug is started early (20, 32). The use of the kallikrein
inhibitor aprotinin (Trasylol
®
), due to allergic reactions,
is questionable (53). Effective bradykinin receptor antag-
onists, already evaluated in humans, appear to be a
promising approach to treatment of HAE attacks (54).
In 1960, Spaulding first showed that methyltestos-
terone was effective in preventing attacks of HAE (38).
In 1976, Gelfand et al. (55) demonstrated that the atten-
uated synthetic androgen danazol also prevented bouts
of angioedema and increased levels of C1-INH. Since,
numerous studies have confirmed the efficacy of attenu-
ated androgens (danazol and, more recently, stanazolol).
During administration of attenuated androgens C4 and
C2 levels rise along with C1-INH levels, however, it is
certainly not necessary to achieve correction of these
proteins for therapeutic success (32, 34, 55). Usually
50% of normal C1-INH function is sufficient to achieve
clinical success, and it is not uncommon to observe
clinical remission without increase of C1-INH activity.
The minimal effective dosage of danazol is patient-
dependent, and varies between 50 mg to 600 mg daily.
Stanozolol, another synthetic attenuated androgen, is
comparable to danazol in efficacy, but with less mas-
culinising potential. Generally a stable C1-INH activity
is obtained within 1 to 2 weeks after start of therapy.
Occasionally alternate-day therapy is possible (34). The
few reports on the safety of long-term treatment for
prophylaxis of HAE have failed to show important
drug-related adverse events (7, 56). In children with
HAE, androgen therapy is generally not recommended
unless attacks are severe and frequent. Because androgens
can induce masculinisation of the female foetus, wher-
ever possible these drugs should not be administrated
during pregnancy (37). However, attenuated androgens
have proved to be safer than expected in pregnancy (32).
Since 1966, two antifibrinolytic drugs – ε-aminocaproic
acid, and its analogue, tranexamic acid – have also been
used successfully in preventing and controlling bouts of
HAE (20, 32-35). Both drugs have been reported to con-
trol attacks of HAE despite no consequent increase in
C4 and/or C1-INH, and probably act through inhibition
of plasmin. Tranexamic acid is effective in significantly
lower dosages (1-2 g/day) than EACE (6-10 g/day) and
is safer as far as side effects are concerned. As a con-
sequence of their potential side effects, e.g., muscle
necrosis and a potential thrombotic effect (4), prescrip-
tion of these agents has diminished in favour of the
attenuated androgens the treatment of choice for severe
HAE. Nevertheless, in a lowest effective dose, EACA
as well as tranexamic acid, constitutes a valuable alter-
native in patients in which attenuated androgens are
contra-indicated and that are suffering from severe or
frequent attacks. Long-term replacement therapy with
purified C1-INH concentrate has been reported to be
effective and well tolerated, especially in patients in
which the other available drugs are contra-indicated or
not tolerated (57). Recombinant cytokine activation of
C1-INH genes, recombinant human C1-INH, recombinant
product of a serpine gene mutated for increased C1-INH
activity, designer molecules with C1-INH activity and
gene therapy, today, remain future considerations.
When C1-INH deficient patients are scheduled for
elective surgery, especially in the oropharyngeal region,
prophylaxis against possible exacerbation is of particu-
lar concern. In such instances, short-term prophylactic
treatment with attenuated androgens, or an increment of
the maintenance dosage, have been demonstrated to be
highly effective (20, 58). Prevention consists of increased
28 HEREDITARY ANGIONEUROTIC EDEMA: REVIEW OF THE LITERATURE
Acta Clinica Belgica, 2000; 55-1
androgen dosage 5-10 days pre-operatively and 3 days
postoperatively (danazol 200 mg t.i.d., stanozolol 1 mg
q.i.d.), eventually in association with fresh frozen plas-
ma shortly prior to intervention (32, 52). Preoperative
administration, especially when time is pressing, as well
as pre-delivery administration of purified C1-INH con-
centrates has also been performed successfully (32, 36,
57, 58). C1-INH does not cross the placental barrier,
therefore, substitution of the mothers will not interfere
with the measurement of C1-INH in the new born.
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Chapter
Der Larynx und Hypopharynx sind Bestandteile des oberen aerodigestiven Trakts und durch ihre Bindegewebselemente und unterschiedlichen Epithelstrukturen eng miteinander verknüpft. Die Anatomie und Histologie beider Organe ist sehr komplex, und Einzelheiten hierzu sind aus den verschiedenen Lehrbüchern und darauf spezialisierten Veröffentlichungen [103, 158, 238, 321, 322] zu entnehmen. An dieser Stelle werden nur besonders wichtige Daten wiedergegeben.
Chapter
Benign pathology of the larynx requiring radiologic evaluation is uncommon. Laryngocele, traumatic pathology and vocal cord paralysis are the most frequent conditions imaged. In this chapter, the imaging findings of benign pathology of the adult larynx are reviewed.
Chapter
The complement system is a vital part of the immune system in humans. It is composed of a group of highly coupled proteins that interact with one another to effect inflammation and the humoral immunity fly. Important aspects of the function of the complement system in triggering action in humans include the following [2]:1. Opsonization of foreign organisms and particles 2. Cytolysis of invading organisms 3. Rendering immune complexes harmless to the body 4. Generation of complement byproducts that act as chemotactic agents that recruit inflammatory cells 5. Anaphylatoxins, which are complement byproducts that stimulate release of chemical mediators such as histamine from mast cells
Article
The hereditary angioedema (HAE) is a rare autosomal dominant disease, characterized by reduced plasma concentration of C1 esterase inhibitor (C1-INH) (type I) or the presence of non functional C1-INH (type II). The clinical manifestations of this disease include recurrent attacks of self-limiting edema affecting face, extremities, gastrointestinal system and upper airways. In this report we describe and discuss the case of a 46-year-old woman, affected by type I HAE, who presented laryngeal edema, responsible for a delayed progressive, massive and irrevocable cerebral edema.
Article
The diagnosis of allergic diseases can be made in different ways. A good history often leads us towards the offending allergen. Nevertheless, the definite etiological diagnosis often needs to be confirmed by additional tests: for inhalational allergy skin testing and determination of specific IgE are usually reliable. High total serum IgE can be associated with false positive specific IgE determinations. In food allergy skin tests are less available. Plant derived products can induce false positive results due to IgE formation to sugar moieties. In drug allergy, in vivo tests might be too hazardous to perform with the culprit drug. In this case unharmful alternatives are tested.
Article
In 1888, Osier reported hereditary angioneurotic edema (HAE) as a disease characterized by familial paroxysmal and localized edema of unknown cause. Donaldson and Evans found that decreases or functional insufficiency of the inhibitor of complement component 1 (C 1-INH) causes HAE which is accompanied with the symptoms of localized edema of the face, head, pharynx, larynx, and joint of the four extremities. In this article, we report a case of hereditary HAE that was confirmed in our hospital. A 48-year-old woman visited Tokyo Dental College Chiba Hospital because of frequent occurrences of facial edema after dental treatment using local anesthesia. The present symptoms started at the age of 38. Her family medical history included, an elder brother who also has a history of edema of the face after the use of local anesthetics. Therefore, HAE was suspected because of her family history of localized facial edema. The results of tests for the complement system are shown in Table 1. Type II HAE was confirmed in the present case, in which the amount of protein was normal whereas the activity was reduced. The patient needed bridge restoration for the left molar mandibular region. We planned to keep her at the hospital until the day after treatment as a precautionary measure to quickly respond to asphyxia which could be caused to laryngeal edema. Intravenous sedation was used to alleviate the mental stress associated with dental treatments. After establishing adequate sedation level, infiltration anesthesia was conducted using 3.6ml of 3% prilocaine containing 0.03IU/ml felypressin solution. Vital teeth preparation was performed without any pain. No evidence of edema or any other abnormal findings was observed on the day of treatment or the subsequent day. Impressions were taken using 1.8ml of 3% prilocaine containing 0.03IU/ml felypressin solution without intravenous sedation. No evidence of edema or any other abnormal findings was observed at this time. An insertion of the bridge was also conducted using 1.8ml of 3% prilocaine containing 0.03 IU/ml felypressin solution without intravenous sedation. The patient felt pain during the treatment, and edema unexpectedly appeared at this time. The patient was immediately admitted to our hospital and received intravenous administration of an anti-plasmin preparation. It is known that epinephrine enhances vascular permeability through an action on vascular endothelial cells. We used prilocaine-felypressin solution, which did not produce attacks of edema previously, for local anesthesia. However, edema unexpectedly developed after the third treatment. This result suggests that pharmacological mechanisms of epinephrine and felypressin may be involved in the present edema. In addition, the patient felt pain during the insertion of the bridge. It should be also considered that in this case, physical and/or mental stress may have triggered the edema under insufficient local anesthesia followed by sympathetic activation. From these findings, it is suggested that adequate local anesthesia using vasoconstrictor free local anesthetic solution such as mepivacaine under adequate conscious sedation may be necessary to prevent the development of HAE attacks.
Article
This article describes a technique for fabrication of a custom tracheostomy obturator for a patient with hereditary angioneurotic edema and a permanent tracheostoma. The impression technique and fabrication of a custom tracheostoma valve retainer for a laryngectomy patient closely mirrors the technique used for fabricating a tracheostomy obturator.
Article
Resumen. Los medicamentos derivados del plasma son un conjunto de concentrados de proteínas preparados a partir de plasma humano que se pueden clasificar en cinco categorías: albúmina, inmunoglobulinas, factores de la coagulación, antiproteasas y adhesivos biológicos. Están indicados en el tratamiento sustitutivo de enfermedades constitucionales o adquiridas de la hemostasia o en el tratamiento de estados patológicos médicos o quirúrgicos. El origen humano y la necesidad de extraer los diferentes productos de mezclas de plasmas provenientes de miles de donantes exigen la aplicación de procedimientos de eliminación e inactivación vírica muy complejos, en constante evolución. A pesar de los progresos considerables en este campo, el riesgo teórico de transmisión de agentes infecciosos conocidos o desconocidos no puede descartarse. Esto debe incitar a actuar con prudencia, evaluando siempre en cada caso el beneficio con respecto al riesgo. En este artículo se describen los principios de purificación, los diversos métodos para garantizar la seguridad biológica y las aplicaciones clínicas de estos productos. También se incluyen los medicamentos recombinantes que completan la gama.
Article
What we now call angioneurotic edema was first adequately described by Quincke,¹ in 1882, as "acute circumscribed edema of the skin." He looked on it as a vascular neurosis and attempted to separate it clinically from all other forms of local edema as a distinct disease. But while to Quincke belongs all the credit of having first presented the subject with the detail and interpretation necessary to its general recognition, he was not the first to observe the condition so carefully as to recognize its individual character. This had been done ten years earlier by Milton,² who recorded his observations in 1876 under the title, "On Giant Urticaria," pointing out clearly that the cases were of a new kind to him and were distinctly different from the severest forms of urticaria as previously described and commonly understood. Had he dignified with a new name the new condition he observed so
Article
Affected persons in three families with hereditary angioneurotic edema completely lack naturally occurring serum inhibitor of C′1esterase. This inhibitor is also absent from some younger relatives who have not yet had typical attacks of swelling. Its absence is characteristic of the hereditary form of angioneurotic edema, for those with nonhereditary types have normal or increased amounts of the inhibitor. Of 500 persons tested, no others completely lacked this inhibitor.
Article
Abstract Five patients with hereditary angioneurotic oedema (HANE) have been treated, in a random double-blind cross-over study, with tranexamic acid (trans-AMCHA). Three patients have reacted positively to the treatment. The positive effect in these cases has been so obvious that a specific effect of trans-AMCHA seems probable even if it cannot be definitely ruled out that spontaneous variations have been the cause of this effect. Therapeutic trials with fibrinolytic inhibitors should be made on patients with HANE.
Article
Five patients with hereditary angioedema (HAE) were studied during attacks and remission as were healthy controls. The high levels of C1/C1-INH complexes, low C4 and high ratio C4 activation products (C4bc)/C4 also differed significantly during remission compared to controls.During attacks C4bc/C4 increased (922–2007; P=0.022, remission versus attacks, median values throughout), C2 and CH50 dropped (111–31%; P=0.043 and 110–36%; P=0.016, respectively), TCC (C5b-9) increased (0.88–1.23 AU/ml; P=0.028). Cleavage of HK increased to be almost complete during attacks (20–90%; P=0.009). While factor XIa/serpin-complexes did not increase, a more than twofold rise in thrombin/antithrombin-complexes (0.20–0.50 μg/l; P=0.009) and in plasmin/alpha-2-antiplasmin-complexes (7.3–17 nmol/l; P=0.028) was observed. For the first time cascade activation in HAE was studied simultaneously, and corroborates that attacks lead to activation of the kallikrein-kinin system, fibrinolysis and early part of the classical complement pathway. In addition, the authors present novel data of terminal complement and coagulation activation, the latter apparently not via FXIa.
Article
A family affected with hereditary angioneurotic edema is reported. The world literature concerning the disease is reviewed. Available nonspecific therapy, including promethazine and methyltestosterone, is discussed.
Article
The authors report the case of a patient with chronic urticaria associated with angioneurotic oedema, in whom the aetiological assessment demonstrated serum alpha-1-antitrypsin deficiency. One of the patient's brothers had also suffered from angioneurotic oedema for several years and presented a low alpha-1-antitrypsin level. In our patient, combined treatment with H1 histamine receptor inhibitor and dapsone allowed control of the mucocutaneous manifestations. Dapsone, which has sometimes been tried successfully in panniculitis associated with alpha-1-antitrypsin deficiency, has a place in the therapeutic armamentarium for urticaria associated with alpha-1-antitrypsin deficiency and can be used after failure of conventional treatment.
Article
The activation of complement component C2 by C1s is a major reaction step leading to the assembly of two related macromolecular enzymes in the classical complement pathway C3 convertase and C5 convertase. The present studies clearly document the smaller fragment, C2b, that results when human C2 reacts with C1s. We have identified and characterized C2b (34,000 daltons) as a single protein on disc electrophoresis and immunoelectrophoresis. C2a (73,000 daltons), the larger fragment from this reaction, has a more acidic nature and C2b is more basic. These fragments can also be detected by their different antigenic determinants. When the C2-C4b complex is activated in the fluid phase by C1s and allowed to decay, it dissociates into C2a and the C2b-C4b complex. Furthermore, when C2 is bound to C4b-Sepharose and then reacted with C1s, only the C2a fragment is released from the solid phase C2-C4b-Sepharose into the fluid phase, and the C2b fragment remains noncovalently bound to C4b-Sepharose. These results suggest that the C2b portion of C2 contains a stable binding site for C4b and, after the decay release of C2a from this C3 convertase, the C2b fragment remains bound. Thus, the decay release of C2a may represent a temperature-dependent dissociation from C2b.