1. www.ijaai.in
Volume 29 / Issue 1 / January-June 2015
ISSN 0972-6691
Indian Journal of
Allergy, Asthma & Immunology
Official Publication of
Indian College of Allergy, Asthma and Applied Immunology (ICAAI)
IndianJournalofAllergy,Asthma&Immunology•Volume29•Issue1•January-June2015•Pages1-???
3. Agarwal and Agarwal: Sporadic nonfamily case of hereditary angioedema type III
47Indian Journal of Allergy, Asthma and Immunology | Jan-Jun 2015 • Volume 29 • Issue 1 47
CASE REPORT
Ms. RA, 38 years, a known case of primary infertility was
first seen on March 31, 2015, for cutaneous angioedema
involving face and torso. She had no urticaria and
had similar symptoms off and on for 4 years (usually
self‑limiting). There was no history of taking aspirin,
ACE inhibitors, angiotensin receptor blockers (ARB’s),
or history of malignancy, autoimmune disease, or drug
causing change in estrogen levels. She had no family history
of similar illness. She was given H1 blockers (ebastine),
H2 blockers (ranitidine), and steroids (deflazacort). She
developed abdominal pain with distention, gaseousness,
vomiting, facial edema, and throat discomfort on April 12,
2015, and was admitted to another nursing home where
she was diagnosed to have sub‑acute intestinal obstruction
and managed conservatively with antibiotics, fluids, and
supportive treatment. She revisited clinic on April 14,
2015, and had mild facial puffiness and lip swelling. She
was suspected to have hereditary angioedema (HAE) and
was further evaluated. Her investigations are tabulated
in Table 1. She developed similar abdominal symptoms
on April 29, 2015, and a contrast‑enhanced computed
tomography (CECT) abdomen was done which showed
multiple segments of thickening of walls of ileum of
varying length (longest being approximately 9 cm) with
resultant luminal narrowing [Figure 1]. She recovered
spontaneously within 3–5 days. On further questioning
she revealed that she had similar mild abdominal pains
off and on since 2003, but it was attributed to mild pelvic
endometriosis diagnosed during her work up of primary
infertility and in vitro fertilization treatment. However,
these two attacks were severe. With normal complement
and C1‑INH (both functional and quantitative) she was
diagnosed to have HAE type III (sporadic case) and started
on prophylactic Danazol treatment. In the meantime other
opinions were sought and she was evaluated for celiac
disease and inflammatory bowel disease and was given
options of capsule video endoscopy and a therapeutic trial
for Crohn’s disease. Barium meal follow through done
on May 11, 2015, and a repeat CECT abdomen done on
May 26, 2015, were normal [Table 2, Figures 2 and 3]. She
is at present on Danazol and had no further episode of
angioedema till end of July 2015.
DISCUSSION
HAE is an autosomal dominant rare, debilitating disease that
impairs quality of life. About 10–20% of people worldwide
will develop an episode of angioedema or urticaria at some
point in their lifetime, women being more prone than men.[1]
The prevalence of HAE is around 1/100,000, and involves
almost all races.[2]
The term “angioedema” describes a
circumscribed edema of the skin, gastrointestinal (GI) tract
Figure 1: Contrast‑enhanced computed tomography
abdomen (coronal view) done on April 30, 2015, showing multiple
segmental ileal luminal narrowing (arrows)
Figure 2: Barium meal and follow through done on May 11, 2015
showing complete resolution of ileal narrowing
Figure 3: Contrast‑enhanced computed tomography abdomen
done on May 26, 2015 showing complete resolution of multiple
segmental ileal narrowing [compare with Figure 1]
4. Agarwal and Agarwal: Sporadic nonfamily case of hereditary angioedema type III
Indian Journal of Allergy, Asthma and Immunology | Jan-Jun 2015 • Volume 29 • Issue 148
or respiratory tract. The majority of cases are HAE, acquired
angioedema (AAE) or idiopathic angioedema (IAE). The
salient features of various types of AE are presented in
Table 3. EP needs to differentiate between histamine and
bradykinin mediated angioedema. In a bradykinin mediated
angioedema there is no itching or urticaria and treatment
with corticosteroids and antihistamines is not effective.
In HAE, there is a mutation in the gene that encodes the
C1‑INH of the complement factor (INHC1), inducing a
reduction in its synthesis (type I HAE) or the formation
of a dysfunctional protein (type II HAE). In 2000, a
new subtype of HAE was described, which is clinically
indistinguishable from the others, predominantly in women,
in which the INHC1 is normal.[3]
This new disorder was
called HAE type III, estrogen‑dependent HAE or HAE
with normal C1 activity (type III HAE). It is very rare and
found predominantly in women and may be due to known
mutations in the factor XII gene (F12) or to unknown
genetic mutations.[4]
Studies have reported first episode
or recurrences associated with estrogen containing oral
contraceptives, estrogen replacement therapy or pregnancy,
thereby suggesting a direct correlation with estrogen levels.
Our patient had no such history but rather had primary
infertility.
In angioedema localized temporary swelling occurs, which
can involve all layers of the skin or walls of hollow viscera,
such as pharynx, respiratory system, or the GI tract.
Symptoms may include peripheral nonpitting edema (skin),
swelling of lips, tongue (opharynx) and genitalia, difficulty
in breathing (larynx), nausea, vomiting, diarrhea, features
of intestinal obstruction, and abdominal pain of varying
degree (GI tract). Abdominal pain may manifest as severe
acute onset abdominal pain, or as chronic recurrent
abdominal pain of moderate severity.[5]
In one study,
misdiagnosis of abdominal symptoms had even led to
unnecessary appendectomy, laparotomy, or both, in 35%
of patients.[6]
However, surgical exploration of abdominal
symptoms should be avoided in the absence of signs of acute
abdomen (i.e., absence of fever, leukocytosis, or peritoneal
signs; presence of bowel sounds).[7]
Our patient had severe
attacks with symptoms consistent with intestinal obstruction
Table 2: Imaging of the patient
Date Test Imaging results
April 30, 2015 CECT abdomen Multiple segments of thickening of walls of
ileum of varying length, longest segment of
approximately 9 cm with resultant luminal
narrowing
May 11, 2015 Barium meal
follow through
Normal. No definite stricture or dilated gut
loop seen
May 26, 2015 CECT abdomen No abnormality seen. Multiple segmental
areas of narrowing seen involving the ileum in
CECT dated April 30, 2015 are no longer seen
CECT ‑ Contrast enhanced computed tomography
Table 3: Mediator, distinguishing features and complement profile in angioedema syndromes
HAE type I HAE type II HAE type III AAE IAE ACE‑I NSAID Allergic AE with urticarial
vasculitis
Mediator Bradykinin Bradykinin Bradykinin Bradykinin Unknown
Nonhistaminergic
Bradykinin Leukotriens Histamine Histamine/
leukotriens
Family history Yes Yes Yes No No No No No Yes/no
Urticaria No No No No Usually No Usually Usually Usually
Location Anywhere Anywhere Anywhere Anywhere Especially lips
and face
Especially lips,
tongue and intestine
Especially
face
Anywhere Usually skin
Age at onset in years 6-20 6-20 6-20 >40 Any Any Any Any >15
C4 Low Low Normal Low Normal Normal Normal Normal Low
C1 INH antigenic Low Normal Normal Low (type I)
Low/normal (type II)
Normal Normal Normal Normal Normal
C1 INH functional Low Low Normal Low Normal Normal Normal Normal Normal
C1q Normal Normal Normal Low (type I)
Low/normal (type II)
Normal Normal Normal Normal Low
C3 Low Low Normal Low Normal Normal Normal Normal Low
HAE ‑ Hereditary angioedema, AAE ‑ Acquired angioedema, IAE ‑ Idiopathic angioedema, ACE‑I ‑ Angiotensin converting enzyme inhibitor, NSAID ‑ Nonsteroidal anti‑inflammatory drug, C1 INH ‑ C1 esterase inhibitor
Table 1: Hematological and other investigations
Date Investigation Result Unit Reference range
March 31, 2015 C3 235.67 mg/dL 75-135
C4 37.49 mg/dL 10-40
TLC 5.5 ×103
/µL 3.5-11.5
Hb 10.7 g/dL 13-16
Platelet count 246 ×103
/µL 150-410
TEC 105 Cmm 20-500
VEC 0 % TEC Nil
Urine Normal
April 14, 2015 C1 esterase inhibitor
Protein (quantitative)
247 mg/L 195-345
C1 INH
Functional
84.8 % 68
April 30, 2015 CRP 26.4 mg/L <5
ESR 18 mm 1 h 0-20
tTG IgA antibodies 1.6 U/mL <12
P ANCA and C ANCA Negative
May 05, 2015 Stool test routine Normal
ESR 22 mm 1 h 0-20
CRP 5.1 mg/L <5
May 06, 2015 ASCA IgA saccharomyces
Cerevisiae
11.2 U/mL <10
ASCA IgG saccharomyces
Cerevisiae
67.8 U/mL <10
CRP 3.1 mg/L <5
TLC ‑ Total leucocyte count, TEC ‑ Total eosinophil count, VEC ‑ Vacuolated eosinophil count,
CRP ‑ C‑reactive protein, ESR ‑ Erythrocyte sedimentation rate, tTG ‑ Tissue transglutaminase
antibody, ASCA ‑ Anti‑saccharomyces cerevisiae antibodies, ANCA ‑ Anti‑neutrophil cytoplasmic
antibody, C1 INH ‑ C1 esterase inhibitor
5. Agarwal and Agarwal: Sporadic nonfamily case of hereditary angioedema type III
49Indian Journal of Allergy, Asthma and Immunology | Jan-Jun 2015 • Volume 29 • Issue 1 49
on two occasions and was even referred to GI surgeon after
CECT showed ileal luminal narrowing at multiple levels.
However, it resolved within 3–5 days and subsequent barium
meal and follow through examination and CECT scan
abdomen did not show any features of intestinal obstruction.
Thus, alternate diagnoses for recurrent abdominal symptoms
should always be considered to avoid unnecessary surgical
procedures as patients presenting only with abdominal
signs and symptoms have been described in literature with
no cutaneous, oropharyngeal or respiratory involvement.[8,9]
The differential diagnosis includes AAE and IAE. In
AAE, there is no familial inheritance, and it can occur at
a later age than HAE. The condition develops as a result
of increased consumption of C1‑INH or impairment of
C1‑INH function due to autoantibody formation. AAE
is divided into four groups: (1) AAE‑I ‑ resulting from
paraneoplastic syndrome or development of auto antibodies
which enhances cleavage of C1‑INH, leading to C1‑INH
dysfunction; (2) AAE‑II ‑ resulting from autoimmune
disease; (3) AAE ‑ associated with sex hormones, especially
during pregnancy; and (4) drug‑induced AAE ‑ particular
associated with ACE INHs or ARB’s.[10]
Our patient had no
such feature to suggest AAE. IAE is usually associated with
urticaria. Thyroid dysfunction is common with this form
and should be ruled out. The mechanism of this disease
is unknown.[10]
Our patient did not had any urticaria or
thyroid dysfunction.
The inheritance pattern of HAE type III has a genetic
polymorphism that contributes to phenotypic diversity of
HAE type III[11]
A family history of angioedema strongly
supports the diagnosis, but it is not required, since
approximately one‑quarter of patients have de novo
mutations. There are reports of nonfamily cases, sporadic,
that could present new genetic mutations, different to those
already described so far and still unknown.[12]
Although
criteria for diagnosis of angioedema caused by C1‑INH
deficiency have been described, no diagnostic criteria have
been defined so far for HAE type III. HAE type III, to date
manifest only in women, and its symptoms closely resemble
those associated with functional C1‑INH deficiency but
occur in the presence of normal C1‑INH concentrations;
the genetic defect responsible is currently unknown.[13]
Genetic tests that could classify her with a genetic alteration
were not performed due to the nonavailability of such tests
in our facilities. Thus, with normal C1‑INH (antigenic
and functional) levels, history of recurrent angioedema,
spontaneous remission over 3–5 days, recurrent abdominal
symptoms with imaging findings, no history/cause to suggest
other causes of angioedema, she was diagnosed as a sporadic
nonfamily case of HAE type III. IAE looked unlikely looking
to absence of urticaria and response to long‑term prophylaxis
with Danazol. She had no further attack till July 31, 2015.
It is also important to recognize that all attacks localized
over the shoulder (face, neck, throat, and respiratory tract)
and all abdominal attacks with pain rated >5 on the visual
analogue scale are considered severe.
Treatment options of HAE involve prophylaxis ‑ both
short‑term and long‑term; and acute treatment.
• Short‑term prophylaxis: Three options of attenuated
androgens, tranexamic acid or C1‑INH concentrate are
available. There is no specific problem for the use of
these drugs for the short‑term in female patients. In case
of short‑term prophylaxis with attenuated androgens,
no virilization has been observed[14,15]
• Long‑termprophylaxis:Attenuatedandrogens (Danazol),
anti‑fibrinolytics (tranexamic acid) and plasma derived
C1‑INH (pdC1‑INH) are used. Attenuated androgens
are highly effective but are accompanied by side effects.
The result of PREHAET study (presented by Bork)
reported a weight gain for 30% of women, virilisation
for 6%, menstrual irregularities for 30%, acne for
7% along with alopecia, hirsutism, and mammary
hypotrophy.[16]
However, they are dose dependant and
can be decreased by titrating the dose to lowest effective
level. Anti‑fibrinolytics have good tolerance, moderate
efficacy and adverse effects as nausea, diarrhea and a
theoretical risk of thromboembolism. pdC1‑INH was
approved by Food and Drug Administration in 2008 for
long‑term prophylaxis. It is not available in India.
Acute treatment
Treatment guidelines for HAE recommend the use of the
bradykinin receptor blocker (icatibant) or the kallikrein
INH (ecallantide) for the treatment of acute attacks.[17]
In the United States, ecallantide and the pdC1‑INH were
approved in 2009, and the bradykinin receptor blocker
icatibant was approved in 2011 for the treatment of
acute attacks of HAE. Since all three are not available in
India, using fresh frozen plasma (FFP) in acute attack is a
reasonable choice and an infusion of 2‑4 U of FFP is useful
in replacing INH levels.[18]
Rarely the swelling can become
worse due to complement factors present in FFP. The only
option for acute settings in our case could have been use of
FFP. Our patient is in long‑term prophylaxis with Danazol.
The major issue still is the difficulty that many patients
have in reaching correct diagnosis and treatment. Deaths
and unwanted surgeries caused by HAE and similar
angioedematous disorders still occur. The EPs, ignoring the
existence of HAE, still label these patients as allergic. We
hope that this case report will help bring more HAE, AAE,
and IAE patients to the correct diagnosis.
On literature search, we did not find any case report of
a sporadic nonfamily case of HAE type III presenting as
abdominal pain with intestinal obstruction in women with
primary infertility.
6. Agarwal and Agarwal: Sporadic nonfamily case of hereditary angioedema type III
Indian Journal of Allergy, Asthma and Immunology | Jan-Jun 2015 • Volume 29 • Issue 150
CONCLUSION AND TAKE HOME
MESSAGE
• HAE with normal C1‑INH (HAE type III) is clinically
characterized by recurrent angioedema affecting the
skin, GI tract, and larynx
• HAE can rarely present as a nonfamily, sporadic case
• HAE should be recognized in its various forms and
especially as a cause of recurrent unexplained abdominal
pain so that unnecessary invasive procedures and
hospitalizationscanbeavoidedandlong‑termprophylaxis
therapy can be administered. Prompt detection and
treatment of this rare disease can significantly improve
patient outcome by minimizing morbidity
• EPs should differentiate between histamine and
Bradykinin mediated angioedema and recognizes
“attacks” that are considered severe.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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