Journal Pre-proof

Angioedema as a systemic disease

Jana Kazandjieva, MD. George Christoff

PII: S0738-081X(19)30146-4
DOI: https://doi.org/10.1016/j.clindermatol.2019.07.035
Reference: CID 7376

To appear in: Clinics in Dermatology

Please cite this article as: J. Kazandjieva and M. George Christoff, Angioedema as a
systemic disease, Clinics in Dermatology(2019), https://doi.org/10.1016/
j.clindermatol.2019.07.035

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 Journal Pre-proof

Angioedema as a systemic disease

Jana Kazandjieva MD,Ph.D.1, George Christoff MD.Ph.D.2

1
Department of Dermatology, Medical University – Sofia, Sofia, Bulgaria
2
Medical University – Sofia, Faculty of Public Health; Acibadem City Clinic Tokuda
Hospital, Sofia, Bulgaria
Corresponding author: tel. +359 887237391, Email adress: janaderm@abv.bg

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Abstract

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Angioedema is a clinical entity defined as self-limiting edema localized in the deeper layers
of the skin and mucosa and lasting for several days. Angioedema can be provoked by
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bradykinin and/or mast cell mediators including histamine. Four types of acquired(AAE) and
three types of hereditary(HAE) angioedema have been identified. The most obvious form of
angioedema associated with other systemic disease is AAE due to C1-inhibitor deficiency. It
e-
is characterized by acquired consumption of C1-INH and various underlying disorders like
multiple myeloma, chronic lymphocytic leukaemia, rectal carcinoma, and non-Hodgkin
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lymphoma. Suspected cases need an accurate differential diagnosis in order to exclude all
other types of AAE and HAE.
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rn

Introduction
Angioedema is a clinical entity defined as a self-limiting edema localized in the deeper layers
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of the skin and mucosa and lasting for several days. For the first time the disease is described
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by Heinrich Quincke (1842-1922) in 1882,1 and since then, it is often referred to as Quincke
edema.
Angioedema is characterized by a vascular reaction of deep dermal, subcutaneous, mucosal
or submucosal tissues with localized increased permeability of blood vessels resulting in
tissue swelling2,3,4,5,6. Angioedema can be mediated by bradykinin and/or mast cell mediators
including histamine7.
A well known and most frequent manifestation of angioedema due to histamine and other
mast cell mediators is the one that occurs as part of urticaria. It is characterized by two signs:
 wheals - edema of superficial skin layers
 angioedema - edema of deep skin layers8.
Bradykinin - mediated angioedema occurs either on a hereditary or acquired basis, due to a
deficiency/defect of C1 inhibitor (C1-INH) or other mechanisms9,10.
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It is obvious that the diagnosis of angioedema needs to be refined by the specification of its
type. If angioedema recurs without significant wheals, the patient should be diagnosed
having angioedema as a disease of its own. Because an accepted classification is absent,
different types of angioedema are not well and easily identified.
Classification
According to the EACCI classification7, angioedema without wheals as a separate disease is
classified on the basis of its cause - acquired or hereditary, and response to treatment. Four
types of acquired(AAE) and three types of hereditary(HAE) angioedema are identified.
Acquired angioedema:
1. Acquired AE with unidentified cause(idiopathic), responding to treatment with
antihistamines - IH-AAE

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2. Acquired AE with unidentified cause(idiopathic), nonresponding to treatment with

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antihistamines - InH-AAE
3. Acquired AE after treatment with Angiotensin Converting Enzyme inhibitors (ACEI)
- ACEI-AAE pr
4. Acquired AE due to C1-inhibitor deficiency - C1-INH-AAE.
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Hereditary angioedema:
1. HAE with autosomal dominant inheritance and C1-inhibitor deficiency (cause: mutations
in SERPING1 gene) - C1-INH-HAE
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1.1. Type 1 with decreased С1-INH plasma levels leading to an increase in

bradykinin formation
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1.2. Type 2 with dysfunctional С1-INH protein

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2. HAE with normal plasma levels of C1-inhibitors due to Factor XII - FXII-HAE(2),
plasminogen(3) or angiopoetin-1 mutations(4),
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3. HAE of unknown reason – U-HAE.

Another similar classification of angioedema is based on the type of mediators responsible
for symptom development 11: bradykinin-induced AE, mast cell mediator induced AE, and AE
due to unknown mediator.

ACQUIRED ANGIOEDEMA
AAE is localized on the face, lips, tongue, extremities, or genital area. Swelling episodes may
have various triggers, such as mild trauma, viral or bacterial infections, cold exposure,
pregnancy, certain foods, or emotional stress. The incidence of edema episodes is
unpredictable and can vary widely.
Acquired angioedema with C1 inhibitor deficiency
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The most obvious form of angioedema related to other systemic diseases is the third form of
AAE, namely AAE due to C1-inhibitor deficiency (C1-INH-AAE)12. The disease was first
described in 197213. The first patient had C1 inhibitor deficiency in combination with
recurrent episodes of angioedema and lymphosarcoma. Currently, C1-INH-AAE is
considered a subset of acquired angioedema. This form of AAE is characterized by acquired
consumption of C1-INH associated with various underlying disorders.
The nature of acquired angioedema with C1 inhibitor deficiency (C1-INH-AAE) is
nongenetic which implies that no mutations in C1-INH gene (SERPING1) and no family
history of angioedema are associated with this disease. In the absence of epidemiologic
studies, the prevalence of C1-INH- AAE in the general population is estimated between
1:100 000 and 1:500 000, based on the experience of identifying one C1-INH-AAE patient
for every 10 HAE patients7. Because the condition remains often unnoticed, the real
prevalence is probably much higher. Persons of any race may suffer from C1-INH-AAE, and

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men and women are equally affected.

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Studies on plasma from patients with C1-INH-AAE indicate consumption of C1-INH and
classic pathway complement components and, during attacks, activation of contact system
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with release of bradykinin which causes angioedema. The lymphoproliferative disease,
frequently found in these patients, could directly contribute to the consumption of C1 and
C1-INH7.
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A few basic elements, characteristic for this type of acquired angioedema have been
described:
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1. negative family history for AE

2. age of onset after the fourth decade of life
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3. acquired deficiency of C1-INH

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4. hyperactivation of the classic pathway of human complement

5. recurrent angioedema episodes.
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C1-INH-AAE is grouped into two different types 14:

1. Type I – associated with lymphoproliferative or autoimmune diseases
2. Type II – associated with autoimmune abnormalities.
C1-INH-AAE Type I and associated systemic diseases
Type I is most commonly related to B-cell lymphoproliferative disorders, but cases with
associated T-cell lymphoma have also been described. Other reported neoplastic disorders for
C1-INH-AAE type I are multiple myeloma, chronic lymphocytic leukaemia, rectal carcinoma
and non-Hodgkin lymphoma. There are some publications stating that myelofibrosis,
Waldenström macroglobulinemia, essential cryoglobulinemia, erythrocyte sensitization,
antiphospholipid syndrome and infections with Helicobacter pylori or Echinococcus
granulosis could serve as a trigger factor for this type of acquired angioedema. One patient
has been associated with liver transplantation. The status of the liver donor was unknown, but
it is speculated that the donor may have been C1-INH deficient.
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The associated diseases may become evident years after the beginning of angioedema. A
2016 study reported that 62.5% of the patients were diagnosed with non-Hodgkin lymphoma
at the onset of angioedema or up to 7 years later15. Patients with C1-INH-AAE Type I should
be checked regularly for the development of malignancy.
The underlying disease may produce idiotype/anti-idiotype antibodie, or other immune
complexes that downregulate C1-INH function. Increased consumption of C1q followed by
C2 and C4 results in the subsequent release of vasoactive peptides that act on postcapillary
venules. Another probable explanation for the development of angioedema is the
overconsumption of C1-INH by neoplastic lymphatic tissue 16.

C1-INH-AAE Type II and associated autoimmune abnormalities

Acquired angioedema type II is not a paraneoplastic syndrome. In type II, a normal 105-kD

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C1-INH molecule is synthesized in adequate amounts. As a consequence of an unknown
cause, a subpopulation of B cells initiates synthesis of autoantibodies directed against C1
inhibitor molecules. These autoantibodies might be of any of the major immunoglobulin
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classes. They attach to the epitopes of the reactive centre of C1-INH and its regulatory
capacity is weakened or nullified(10). In all reported cases, C1-INH circulates in the blood in
a form that has been cut down by target proteases to a 95-kD fragment. Due to the higher
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affinity of the autoantibody to native C1-INH, the 95-kD antibody/C1-INH complex
dissociates, and the freed antibody can bind to another native C1-INH molecule, further
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depleting C1-INH.
In some cases, an overlap between type I and II may occur. Patients with acquired
angioedema type I may initially present with autoantibodies to C1-INH, or the autoantibodies
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may develop as the disease progresses. Features of C1-INH-AAE Type I and C1-INH-AAE
Type II has been noted, particularly in patients with monoclonal gammopathy of
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undetermined significance (MGUS).

C1-INH-AAE with autoantibodies and with lymphoproliferative diseases largely overlaps
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and should be considered the same disease. Other conditions, mainly SLE, are reported in
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C1-INH-AAE, which appears as a syndrome with different possible associations; however,

20 of the 180 cases reported in the literature had no underlying disease associated with their
C1-INH-AAE7.
Acquired angioedema with C1 inhibitor deficiency bgins after the age of 40 years in 94% of
patients. Family history of angioedema is never present.
C1-INH-AAE is clinically characterized by episodes of transient nonpitting asymmetric
oedema. The lesions are nonpruritic and painless. Edema can occur anywhere in the body and
typically last for several days. It is usually localized to the face, lips, tongue, extrremities, and
genitals. In C1-INH-AAE, swelling involves the face more often than the extremities, in
contrast to HAE type 1 and 2, where edematous changes of the extremities are more typical.
Gastrointestinal swelling attacks are less common in C1-INH-AAE patients compared to C1-
INH-HAE patients. In most of the patients, the edema of the subcutaneous and/or
submucosal tissue appears without wheels, although a patient with a chronic lymphatic B cell
leukaemia who suffered from both C1-INH-AAE and chronic spontaneous urticaria has been
described17.
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In patients with intestinal edema, colicky abdominal pain, nausea, vomiting, and diarrhea
could be observed. This abdominal pain is less reported in AAE (30-50%) when compared
with HAE (up to 80%). Life-threatening edema of the upper respiratory tract as a clinical
presentation of C1-INH-AAE has also been described. Around 50% of patients with C1-INH-
AAE experience upper airway edema 18.
Diagnosis
Testing for C1-INH deficiency is performed by measuring C1-INH antigen level, C1-INH
function, and C4 levels in plasma. Qualitative and functional values of C1-INH should be
obtained. Test results for acquired angioedema types I and II indicate usually low C1-INH
level; low C1q; low C4 and C2 levels. Acquired angioedema type II shows positive
immunoblot assay findings for the 95-kD C1-INH cleavage product. An enzyme-linked
immunosorbent assay (ELISA) has been developed that measures the neutralizing capacity of
anti-C1-INH antibodies in plasma 19.

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Other laboratory findings are related to the associated illnesses. During attacks of
gastrointestinal edema, abdominal ultrasonography or computed tomography scanning may
show edematous thickening of the intestinal wall, a fluid layer around the bowel, and large
amounts of free peritoneal fluid. pr
Histologic findings are indistinguishable from other angioedema types. Features include
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sparse perivascular mononuclear cell infiltrate and reticular dermal, subcutaneous, or
submucosal edema. Vasodilation may be seen.
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All patients diagnosed with C1-INH-AAE should be assessed for an underlying

lymphoproliferative disorder. Regular check-ups are recommended if at the time of diagnosis
no lymphoproliferative disorder is found. C1-INH-AAE should always be considered in
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patients in the fourth decade of their life with recurrent episodes of angioedema without
wheels and without family history for angioedema.
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Treatment
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Treatment of C1-INH-AAE should consider the underlying disease as well as the frequency
and severity of angioedema. Curing the underlying disease can cure angioedema, and this
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option should be considered. Symptomatic treatment for angioedema recurrences can be

provided using bradykinin-targeted drugs.
The edema is usually unresponsive to antihistamine therapy. AAE may stop if the underlying
disease is treated, but some patients continue to experience episodes of edema despite the
treatment. Treatment focuses on control of the clinical findings by regulating bradykinin
activity using therapies found to be effective in HAE (C1-INH concentrate, icatibant,
ecallantide, tranexamic acid, androgens).
Treatment for angioedema symptoms in patients with C1- INH-AAE has used C1-INH
replacement therapy. The majority of patients respond positively, but some may be resistant
to this treatment due to an extremely rapid catabolism of C1-INH.
Avoidance of triggers (social stressors, trauma, exogenous estrogens, tamoxifen, ACEIs)
prevents, or reduce the frequency(7). Rituximab (monoclonal antibody against lymphocytes
B-CD20) may be a promising therapy and has been used successfully in a few cases.
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The prognosis depends on the control of the underlying disorder20.

In the differential diagnosis all other forms of AAE should be considered:
Idiopathic histaminergic acquired angioedema (IH-AAE)
Histamine-mediated AAE is often accompanied by an urticarial rash(Fig.1). The combination
of spontaneous urticaria and angioedema with duration of more than 6 weeks belongs to the
clinical spectrum of chronic spontaneous urticaria. This type of angioedema is provoked by
allergic or nonallergic stimuli, which usually are unrecognized.
Because continuous administration of an antihistamine stops disease recurrences in a
significant proportion of the patients, this this type of angioedema is defined as
‘histaminergic’. The term indicates for the significant role of the cutaneous mast cells and/or
the blood basophil degranulation and mediator release. Bradykinin or other vasoactive
substances are not predominantly released.

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Histamine release suggests an allergic cause. Very often, the starting point in the evaluation
of patients with angioedema is to identify such a cause. Allergy is suspected if the recurrence
of symptoms is sequential, related to an exogenous stimulus and confirmed by a positive skin
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prick test and/or detection of clinically significant specific IgE. Stimuli, such as medication
and/or foods, insect bites/stings, or other environmental allergens are frequently involved in
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patients with acute angioedema, but only in a minority with recurrent attacks. Strong causal
relationship between infection or autoimmune disease and angioedema is, however,
frequently difficult to confirm. When allergy and other causes have been ruled out and an
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etiology cannot be identified, the histaminergic angioedema is defined to be idiopathic or

spontaneous.
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Clinical presentation
Data on clinical presentation of this form of angioedema are scarce. The following
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description is based on the discussion among experts7. IH-AAE develops rapidly; its
maximum is within 6 h; precipitating factors are not identified; drug history is irrelevant; the
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face is mostly affected; gastrointestinal and laryngeal mucosa are spared and death due to
the angioedema has not been reported; there is no preferred age for onset; attacks are
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prevented by antihistamine and respond to corticosteroids and epinephrine as acute

treatment; family history for angioedema is negative; there are no associated diseases.
Diagnosis
Major diagnostic tools include exclusion of potential causes of angioedema based on the
clinical features: causative agents, associated autoimmune/infectious disease, C1-INH
deficiency, and mutation in factor XII. In the absence of an algorithm specific for
angioedema, it is reasonable to implement urticarial diagnosis guidelines for diagnosis of
urticaria8.
IH-AAE is the most common form of angioedema with some of its clinical and pathogenetic
features similar to idiopathic recurrent urticaria. It is diagnosed on clinical features, exclusion
findings, and therapeutic response. Antihistamine and corticosteroids represent the basic
treatment.
Idiopathic nonhistaminergic acquired angioedema
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This is an angioedema type which is nonfamilial and nonhereditary. Known causes have been
excluded as for IH-AAE, but recurrences persist upon antihistamine treatment. There are not
many medical papers matching the terms idiopathic, nonhistaminergic, and angioedema. A
number of experts belief strongly that it could encompass a distinct, homogeneous group of
patients which is why they are trying hard to provide a definition of this type 7. For the first
time the term is used for describing a group of patients with angioedema and a remarkable
response to a prophylactic course of tranexamic acid 21. A favorable effect of tranexamic acid
was reported in another group of angioedema patients with similar characteristics, but defined
as ‘sporadic idiopathic bradykinin angioedema’ 22. The term ‘bradykinin-mediated’
sometimes stands for ‘nonhistaminergic’ implying that bradykinin mediates this angioedema.
Experimental evidence that bradykinin is involved in the pathogenesis of this type is still
limited. Additional evidence supportive of bradykinin as the mediator comes from case
reports showing efficacy of the bradykinin receptor antagonist icatibant in reverting
angioedema, irresponsive to antihistamine7.

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Clinical presentation
Only two limited series of patients are found in the literature to be considered representative
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of InH-AAE. There is a slightly higher frequency of male gender and age of onset is between
36 and 42 years. The most common symptom location is facial(Fig.2., Fig.3.), followed by
upper airways’ and abdominal involvement. Invasive management (endotracheal intubation)
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for upper airway edema was reported for a single patient in the Italian group. The mean
duration of symptoms is below 48 h and the frequency of recurrences high, with more than
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half of the patients needing continuous prophylaxis with tranexamic acid.

Diagnosis
The first diagnostic step for this type of angioedema is clinical history. The diagnosis is
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based on the patient’s negative response to continuous antihistamines treatment.

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Treatment
There is no conclusive evidence for an effective treatment for attacks of idiopathic
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nonhistaminergic angioedema. Efficacy of tranexamic acid has been reported in two above
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mentioned case series, but no detailed data are available.

Acquired angioedema related to angiotensin- converting enzyme inhibitors (ACEI-AAE)

ACE inhibitors are an unpredictable and important cause for the appearance of AAE. This is
a well-known side effect as a result of the diminished break down of bradykinin. ACE is
involved in the breakdown of bradykinin to inactive peptides. Its inhibition results in elevated
plasma levels of bradykinin that further increase during ACEI-AAE. ACEI typically trigger
angioedema without urticaria. Spontaneous recurrence of angioedema is possible even
months after stopping the drug intake. Angioedema associated with angiotensin receptor
blockers (ARB’s) has been occasionally reported. Recently cases of angioedema were
described after intake of ACEI and antidiabetic drugs(inhibitors of dipeptidyl peptidase-
4(DPP-4). These drugs combinations also lead to increased bradykinin levels in the blood.
Other reasons for drug-induced angioedema are the neprilysin inhibitors, which also cause
high bradykinin levels in the blood.
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Incidence
Analysis of large cohorts of hypertensive patients suggests angioedema to occur in <0.5% of
patients taking ACEI, but 3–4.5-fold more often in black than in Caucasian subjects.
Clinical symptoms
Acquired angioedema related to angiotensin-converting enzyme inhibitors is more frequent
in women than in men and in individuals over 65 years old. The latency between the
initiation of ACEI therapy and the onset of symptoms can vary greatly from a few hours to
several years, but it is more likely to occur early after initiation of ACEI therapy. Acquired
angioedema related to angiotensin-converting enzyme inhibitors is usually observed on the
face, followed by lips, eyelids, tongue, neck, and upper airways. ACEI-induced
gastrointestinal angioedema has rarely been reported. Deaths from laryngeal edema due to
ACEI-AE have been reported. The episodes of angioedema may persist for several months

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after withdrawal of the ACE inhibitor without undermining the validity of the drug-related

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diagnosis.
Diagnosis
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There is no test specifically modified during ACEI-AAE, and therefore, it is diagnosed upon
manifestation of not otherwise explained angioedema in patients taking ACEI.
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Therapy of ACEI-AAE
To prevent ACEI-AAE recurrences, the drug should be immediately discontinued. ACEI
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withdrawal is not, however, 100% effective. On the other hand, continued use of ACEI in
spite of angioedema results in a marked increase in the incidence of recurrent angioedema
with serious morbidity. The reason for persistence of angioedema after ACEI withdrawal is
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not clear. Pathophysiology suggests that bradykinin-targeted drugs, licensed to treat HAE
due to C1 inhibitor deficiency, could be effective to reverse symptoms in ACEI-AAE. Due
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to the lack of efficacy of corticosteroids and epinephrine, some of them have been used off
label in ACEI-AAE7.
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In most patients with ACE inhibitor-related angioedema, symptoms disappear or are

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drastically reduced after stopping the ACE inhibitor. Individuals who do not improve even
after several months of stopping the ACE inhibitor are likely to have an alternative cause for
their angioedema and were coincidentally taking an ACE inhibitor. There are no routine
investigations to distinguish responders from non-responders to ACE inhibitor withdrawal. If
the ACE inhibitor is responsible but is not withdrawn, the attacks may become more severe
and frequent. ACE inhibitors are contraindicated in patients with a history of angioedema and
an alternative antihypertensive drug should be substituted.

The differential diagnoses of AAE include also the forms of HAE as mentioned below.
Because the pathophysiology and the management of these clinical forms are different
from those of AAE, it is important to determine the correct diagnosis.

HEREDITARY ANGIOEDEMA
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Different forms of hereditary angioedema (HAE) are currently recognized and identified
genetically. The forms of HAE with normal C1-INH (HAE-FXII, HAE-ANGPTI, HAE-
PLG,HAE-UNK) share some clinical features and, possibly, therapeutic options11.
Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE)
Hereditary angioedema with C1-INH deficiency (C1-INH- HAE) is a autosomal dominant
orphan disease with minimal prevalence varying from 1.09/100 000 to 1.51/100 000
inhabitants23. C1-INH-HAE is due to one of more than 450 different mutations in one of the
two alleles of the SERPING1 gene, which codes for C1-INH. Several homozygous mutations
were described, predominantly in patients with parents who are close blood relatives.
Structural abnormalities in these patients are very heterogeneous, and prevalence of de novo
mutations is around 25% of cases.
C1-INH is a serine protease inhibitor (SERPIN) and the major inhibitor of several

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complement proteases (C1r, C1s, MASP 1 and 2) and contact-system proteases (plasma

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kallikrein and coagulation factor XIIa) as well as a relatively minor inhibitor of the fi-
brinolytic protease plasmin. Mutations in SERPING1 result in reduced plasma levels of
C1-INH and facilitated release of bradykinin which is the key mediator of this type of
angioedema10.
Two phenotypic variants have been described:
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 Type I is a quantitative decrease in C1-INH with a consecutive diminished functional
activity (C1-INH-HAE type I)
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 Type II is distinguished by normal or high levels of dysfunctional C1-INH.

Clinical presentation and systemic involvement
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C1-INH-HAE is clinically manifested by recurrent, localized subcutaneous or submucosal

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oedema lasting for 2–5 days. The most commonly involved organs are the skin, upper
respiratory and gastrointestinal tract. The clinical expression is highly variable from
asymptomatic cases to patients suffering from disabling and life-threatening attacks. Since
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nearly all patients with C1- INH-HAE present recurrent episodes of abdominal pain due to
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temporary bowel obstruction as a consequnce of mucosal oedema, it is common that they

often undergo unnecessary surgery misdiagnosing for surgical emergency a gastrointestinal
angioedema 24,25.
Diagnosis
C1-INH-HAE is suspected on the basis of the above mentioned symptoms and a positive
family history (although this may not be present in up to 25% of patients), onset of symptoms
in childhood/adolescence, failure to respond to antihistamines, glucocorticoids, or
epinephrine, presence of prodromal signs or symptoms before swellings, and/or the
absence of urticaria (wheals). Diagnosis, however, needs laboratory confirmation.
Measurements of serum or plasma levels of C1-INH function, C1-INH protein, and C4 are
used. In HAE-I, which comprises about 85% of patients, both, the concentration and
function of C1-INH are low. In HAE-II, C1-INH concentrations are either normal or
elevated, whereas C1-INH function is reduced.Patients with C1-INH-HAE present with low
C4, and to a lesser extent low C2, because of consumption due to the activation of the
classical complement pathway lacking its physiological inhibitor C1-INH. Measurement of
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C4 levels is used for screening of C1-INH-HAE because it is decreased even in between

attacks and only exceptionally can be normal. C4 levels are usually low in HAE-I/II
patients, but its sensitivity and specificity are limited. Diagnosis is confirmed by the evidence
of plasma C1-INH levels below 50% of the normal values 26.
Sequencing of the SERPING1 gene can be supportive in the diagnostic workup of some
HAE-1/2 patients (including prenatal diagnosis); however, biochemical C1-INH testing is
effective and less expensive than genetic testing11.
The WHO 1st international standards for C1-inhibitor, plasma, and concentrate was
established in 201127. Diagnosis of C1-INH-HAE should be based on two reduced readings
of C4 and quantitative and/or functional C1-INH, separated by 1–3 months. The constellation
for the diagnosis of C1-INH deficiency has a specificity of 98–100% and a negative
predictive value of 96%28,29.

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Treatment

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Treatment objective of C1-INH-HAE patients is to avoid mortality and reduce morbidity.
Several international consensus papers, released since 2004, guide the treatment of C1-INH-
HAE 30, 31,32, 33, 34, 11
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Upon being diagnosed as C1-INH-HAE, all patients should have readily available, a drug of
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proved efficacy in reverting attacks. The first step to disease control is to administer this
drug as soon as the patient realizes that angioedema symptoms start to develop. If reduction
of disease burden and significant improvement of the quality of life are not achieved by this
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approach, continuous prevention treatment should be considered. Antifibrinolytic agents,

attenuated androgens, and plasma-derived C1-INH are available for this approach.
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Plasma-derived C1- INH, given at doses effective for on demand and as close as possible to
the procedure, appears as the most rational approach because it is promptly effective and has
a sufficient half-life7.
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Hereditary angioedema with normal C1 inhibitor and factor XII mutation (FXII-HAE) and of
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unknown origin (U-HAE)

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From 1985 to 2006, patients of both sexes with HAE and normal C1-INH have been
described. They were members of 11 families. Patients presented with recurrent angioedema
of the skin associated with relapsing episodes of abdominal pain attacks and episodes of
upper airway obstruction. In 2006, a new group of patients with HAE and normal C1-INH
was identified. The cause of the disease in this case is believed to be two different missense
mutations. The location of these mutations was the same locus, as the Hageman factor, or
coagulation F12 gene.7.
Clinical presentation
The clinical symptoms include recurrent skin swellings, abdominal pain attacks, tongue
swelling, and upper airways edema. No difference in clinical symptoms due to the presence
of F12 gene mutations has been identified 35.
Urticaria does not occur at any time in any of these patients. The skin swellings typically
last 2–5 days; they affect mainly the extremities and the face. The abdominal attacks
likewise last 2–5 days and are manifested as severe crampy pain7.
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Diagnosis
Diagnosis of U-HAE is based on clinical findings and requires that patients have the specified
clinical symptoms, one or more family members, affected with these symptoms, do not have
familial and hereditary chronic urticaria with urticaria-associated angioedema, normal C1-
INH activity and protein in plasma, and no HAE-associated mutation in F12 gene. FXII-HAE
has analogous clinical criteria, but with the presence of an HAE- associated mutation in F12
gene.
The laboratory diagnosis of FXII-HAE is purely genetic, while there are no confirmatory
laboratory tests for U-HAE.
Therapeutic approach
Patients with U-HAE/FXII-HAE do not respond to corticosteroids and antihistamines. Based
on the presumed pathophysiology, several potential treatment options are available, including

f
C1-INH agents, icatibant, ecallantide, progesterone, danazol, and tranexamic acid 7, 11.

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The 2017 revision and update of the international WAO/EAACI guideline for the
management of hereditary angioedema11 describes three levels of treatment of HAE.
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On-demand treatment: itt is recommended that all attacks be considered for on-demand
treatment and any attack affecting or potentially affecting the upper airway should be treated
e-
as early as possible. HAE attacks may be treated with either C1-INH, ecallantide, or icatibant.
Intubation or surgical airway intervention are considered early in progressive upper airway
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edema. It is recommend that all patients have sufficient medication for on-demand treatment
of two attacks and carry on-demand medication at all times.
Pre-procedural (short-term) prophylaxis: Short-term prophylaxis before procedures that can
al

induce an attack is recommended.

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Long-term Prophylaxis: Long -term prophylaxis should be considered for patients who face
events in life that are associated with increased disease activity. Patients are evaluated for
long-term prophylaxis at every visit. Use of C1-Inhibitor for first line long term prophylaxis
u

is recommended. Androgens as second-line long-term prophylaxis are suggested.

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Conclusions
Among the many clinical forms of angiodema ,only the Acquired Angioedema due to C1-
inhibitor deficiency has a direct link to other systemic diseases like multiple myeloma,
chronic lymphocytic leukaemia, rectal carcinoma and non-Hodgkin lymphoma. In such cases,
a precise differential diagnosis should be done in order to exclude all other types of AAE and
HAE.

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Fig. 1. Idiopathic histaminergic acquired angioedema

accompanied by an urticarial eruption

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Fig. 2. Idiopathic nonhistaminergic acquired angioedema
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Fig. 3. Idiopathic nonhistaminergic acquired angioedema
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Figure 1
Figure 2
Figure 3