Uploaded by Dr Ravindra Kumar

04 Hereditary angioedema in a young male R1

Peer Reviewed Article
Abhishek Agarwal1
Sony Vyas1
Abhishek Singhai1
Ravindra Kumar 2
1. Department of Medicine, Sri Aurobindo Medical College and PG Institute, Indore, Madhya Pradesh, India
2. Central Research Laboratory, Sri Aurobindo Medical College and PG Institute, Indore, Madhya Pradesh, India
Email | [email protected]
Hereditary angioedema (HAE) is a rare debilitating autosomal dominant disorder caused by mutations in
the C1-inhibitor gene that results in increased bradykinin levels. It is usually misdiagnosed as histaminergic
angioedema which occurs more commonly and is associated with urticaria. We report this disorder in a young
male who presented to us with dyspnoea, recurrent bouts of painful swelling involving various parts of body
and abdominal cramps without any signs of urticaria. The patient was diagnosed as HAE Type I based on
history, poor response to treatment of histaminergic angioedema and low C4, C1-INH antigenic levels.
KEYWORDS: Hereditary angioedema; C1-esterase inhibitor; angioedema
ereditary Angioedema (HAE) is a rare disorder (1 in
50 000) characterised by periodic episodes of pain­
ful, non-pitting, subcutaneous or submucosal oedema
ing the airway, face, abdomen, genitalia and
extremities without any signs of urticaria.1 It is a lifelong
disease with an onset in early childhood; symptoms worsen
during puberty with a high variability and unpredictability in
severity and frequency of manifestations.
A 20-year-old male presented to the emergency department
complaining of tightness of his throat, shortness of breath,
dysphagia with inability to clear his saliva, facial swelling and
abdominal cramps. The patient had no history of any drug
reaction or similar type of illness among family members.
On reviewing past history, he reported intermittent bouts of
abdominal pain with non-pitting painful swelling involving
numerous parts of body (face, neck, back and peripheral
extremities). There was no history of urticaria. He had
experienced an episode once every six months that lasted
for three to four days without treatment from the age of 14
years. His vital signs were all normal except for a BP of
140/90 mmHg and saturation on 90% in room air.
He had oedematous swelling of the face and neck that
was most pronounced on the lips. The swelling was
neither painful nor pitting on palpation, was not warm to
touch nor erythematous. There was hoarseness of his
voice and an oedematous uvula. On arrival, the patient
was managed with intranasal oxygen, intravenous anti­
histamine (diphenhydramine hydrochloride 50 mg), steroid
Current Allergy & Clinical Immunology | March 2016 | Vol 29, No 1
(methyl­pre­dnisolone 60 mg) and epinephrine (1 : 1 000)
0.5 ml given intramuscular (IM) without any symptomatic
relief. However, his airway and facial symptoms showed
a marked improvement after an infusion of fresh frozen
plasmas (FFPS) and the patient was symptom-free within
two days.
The patient’s baseline laboratory results were normal
except the complement study which revealed C4 <5.9 mg/
dl (normal 15–48 mg/dl) and C1-inhibitor antigenic levels
65 mg/ℓ (normal 195–345 mg/ℓ) with normal C3 and C1q
levels. On the basis of the history and presentation,
response to FFPS and these laboratory parameters (low
C1-INH antigenic levels, low C4 levels with normal C1q
levels), we made the diagnosis of Type 1 HAE. He was
discharged on danazole 200 mg twice daily. Danazole
was stopped after three months by tapering the dosage,
however, the patient started having bouts of attacks of
HAE after lowering the dose of Danazole. Thereafter the
patient was on a continued dose of danazole 200 mg twice
a day.
HAE is an inherited autosomal dominant trait caused by
genetic deficiency or dysfunction of C1-INH that may cause
life-threatening and disabling symptoms. Patients typically
present between 5 and 11 years of age.2 A large number of
patients from Germany displayed a mean age of onset at
11.2 years, with almost 90% of patients experiencing onset
of symptoms by the age of 20 years.3
C1-esterase inhibitor belongs to a class of protein
enzyme inhibitors called ‘serpins’ (serine protease
inhibitor – SERPIN), which control different proteases
involved in the complement, kinin/contact, fibrinolytic and
coagulation systems.1 The majority of the HAE cases
show a familial pattern of inheritance, whereas 25% are
due to spontaneous mutations. Deficiency or dysfunction
of C1-INH and the lack of inhibition of the contact kinin
system causes excessive bradykinin production leading to
generation of cyclic guanosine monophosphate (cGMP),
nitric oxide and prostacyclin. This results in increased
vascular permeability and subsequent tissue oedema.
HAE is caused by a quantitative (Type I) or qualitative (Type
II) deficiency of C1-esterase inhibitor (C1-INH) caused by
mutations of the C1-INH gene. Type I HAE accounts for
85% of cases and is characterised by low plasma levels
of C1-INH such as those found in our patient. Type II HAE
is characterised by normal to elevated plasma levels of a
dysfunctional C1-INH and accounts for the remaining 15%
of cases.4 A rare variant Type III HAE with similar clinical
manifestations to Type I and 2, but normal C4 and C1-INH
antigenic levels and function, has been described. A subset
of these patients have a mutation in Hageman factor
(i.e. coagulation factor XII protease) but the underlying
mechanism in the majority of these patients is unknown.
Prompt diagnosis of HAE is important as recent studies
show a significantly increased risk of mortality due to
asphyxiation of upper airway during laryngeal attacks.5
The diagnosis in the patient was based on the history
of recurrent symptoms with onset during adolescence,
absence of urticaria, failure to respond to the appropriate
treatment of histamine-associated angioedema that,
however, was resolved with the use of FFPS and a
complement study typical of Type 1 HAE. Of note is the
negative family history which suggests a de novo mutation
in this patient.
Management of HAE involves treatment of the acute attacks,
short-term and long-term prophylaxis. Bradykinin in the
primary mediator of HAE and treatment of this condition is
targeted towards replacement of the C1-INH, inhibiting the
formation of bradykinin or its action on its receptor. Plasma
derived C1-INH and recombinant form of human C1-INH
has recently been approved for acute treatment of HAE
in adults and adolescents. Cinryze™ brand of C1 inhibitor
may be used for preventing HAE attacks. Berinert® brand of
C1-inhibitor may be used treating acute abdominal, facial
or laryngeal HAE attacks. Both drugs are administered
intravenously and are approved for home infusion.6
Ecallantide and icatibant are both kinin-pathway modu­
lators, but only ecallantide is currently FDA approved for
the acute treatment of HAE attacks in children of 12 years
of age and older.7 Fresh frozen plasma may be used as a
second line of treatment as active C1-INH is an ingredient
of FFP.8 In the past, effective prophylactic therapy (short
and long term) has long been provided by androgens (such
as danazole) and antifibrinolytics (such as tranexamic
acid), but their use is limited by troublesome side-effects.
Our case highlights the importance of making the correct
diagnosis of this rare disorder as its management varies
significantly from histamine-induced angioedema and
delay in treatment can be potentially fatal.
The authors declare no conflict of interest with respect to
the contents of this article.
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Current Allergy & Clinical Immunology | March 2016 | Vol 29, No 1
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