Hereditary angioedema

 Hereditary angioedema (HAE) is a disorder that results in recurrent attacks of

severe swelling. The swelling most commonly affects the arms, legs, face,
intestinal tract, and airway. Itchiness does not typically occur. If the
intestinal tract is affected abdominal pain and vomiting may occur. Swelling
of the airway can result in its obstruction
 There are three main types of HAE. Type I and II are caused by a mutation in
the SERPING1 gene that makes the C1 inhibitor protein while type III is often
due to a mutation of the factor XII gene. This results in increased amounts of
bradykinin which promotes swelling. The condition may be inherited from a
person's parents in an autosomal dominant manner or occur as a new
mutation. Triggers of an attack may include minor trauma or stress, but often
occurs without any obvious preceding event. Diagnosis of type I and II is based
upon measuring C4 and C1-inhibitor levels.
 C1-INH is a member of the serpin family of protease inhibitors, as are alpha-
antitrypsin, antithrombin III, and angiotensinogen. These proteins
stoichiometrically inactivate their target proteases by forming stable, one-to-
one complexes with the protein to be inhibited.
 Within the complement system, C1-INH blocks the activation of C1 and the rest
of the classic complement pathway by binding to C1r and C1s. Without C1-INH,
unchecked activation of C1, C2, and C4 occur before other inhibitors (C4-
binding protein and factors H and I) can halt the cascade.
 C1-INH also inhibits components of the fibrinolytic, clotting, and kinin
pathways. Specifically, C1-INH inactivates plasmin-activated Hageman factor
(factor XII), activated factor XI, plasma thromboplastin antecedent (PTA), and
kallikrein.
 So defect of the C1-INH will overstimulate the classic complement pathway
without inhibition and produce large amounts of bradykinin. Which is an
powerful inflammatory agent that causes the following symptoms.
Signs and symptoms
 Nonpitting cutaneous swelling is the most commonly reported symptom, and
it mainly affects the extremities, the genitalia, and the face.
 Recurrent swelling in the extremities, genitals, face, lips, larynx or GI tract.
 Acute abdominal pain, nausea, and vomiting (The abdominal pain is caused by
edema of the mucosa of any portion of the gastrointestinal tract.)
 Laryngeal edema is the most feared complication of HAE and can cause an
immediate life-threatening emergency.
 Laryngeal edema may progress rapidly through mild discomfort to complete
airway obstruction, usually over a period of hours.
 Mucosal edema of the bladder or urethra can result in urinary retention,
stammering, pain, or anuria.
Diagnosis
 HAE should be considered if a patient presents with:
 Recurrent angioedema (without urticaria)
 Recurrent episodes of abdominal pain and vomiting
 Laryngeal edema
 Positive family history of angioedema
 A blood test, ideally taken during an episode, can be used to diagnose the
condition. Measure: serum complement factor 4 (C4), C1 inhibitor (C1-INH)
antigenic protein, C1 inhibitor (C1-INH) functional level if available. Analysis
of complement C1 inhibitor levels may play a role in diagnosis. C4 and C2 are
complementary components.
Management
 Most acute treatment consists of C1 inhibitor concentrate from donor blood,
which must be administered intravenously; however, fresh frozen plasma
(FFP) can be used as an alternative, as it also contains C1 inhibitor.
 Other treatment modalities can stimulate the synthesis of C1 inhibitor, or
reduce C1 inhibitor consumption. Purified C1 inhibitor, derived from human
blood.
 The medication ecallantide inhibits plasma kallikrein.
 Icatibant inhibits the bradykinin B2 receptor.
 During an attack supportive care such as intravenous fluids and airway
support may be required(tracheal intubation). The medication C1 inhibitor
can be used for both prevention and treatment.
Quincke's edema,
 is an area of swelling of the lower layer of skin and tissue just under the skin or mucous membranes.
The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated
with hives, which are swelling within the upper skin. Onset is typically over minutes to hours.
 Etiology
 More than 40% of chronic angioedema is idiopathic. Trauma, surgical procedures, and stress are
common nonspecific triggers for angioedema attacks.
 Angioedemas with identifiable etiologies include those caused by the following:
 Hypersensitivity (eg, food, drugs, or insect stings)
 Physical stimuli (eg, cold or vibrations)
 Autoimmune disease or infection
 ACE inhibitors
 NSAIDs
 C1-INH deficiency (hereditary and acquired)
 Angioedema is a result of the fast onset of an increase in local vascular permeability in subcutaneous
or submucosal tissue. Histamine and bradykinin are the most recognized vasoactive mediators.
Mechanism.
A-mast cell
mediated

B-kinin
mediate
d
Signs and symptoms
 Angioedema may affect many organ systems. Visible swelling is common in
peripheral angioedema. It is often associated with local burning sensation and
pain without pronounced itchiness or local erythema. The most commonly
involved areas are:
 Peripheral swelling: skin and urogenital area (e.g., eyelids or lips, tongue, hands, feet,
scrotum, etc.)
 Abdomen: Abdominal pain (sometimes it can be the only presenting symptom of
angioedema)
 Larynx: Throat tightness, voice changes, and breathing trouble (indicators of possible
airway involvement), potentially life-threatening.
Angioedema can be life-threatening when it involves the larynx and upper airway. It
can cause trouble breathing, asphyxia, and even death. Throat pain or discomfort,
dysphonia, and dysphasia may indicate laryngeal involvement. Asphyxiation due to
laryngeal edema yields a 3-40% mortality.
Airway swelling can make intubation difficult. This may increase the risk of vocal
cord damage during intubation
Diagnosis
 The diagnosis is made on the clinical picture.
 Routine blood tests (complete blood count, electrolytes, kidney function,
liver enzymes) are typically performed. Mast cell tryptase levels may be
elevated if the attack was due to an acute allergic (anaphylactic) reaction.
 When the patient has been stabilized, particular investigations may clarify
the exact cause; complement levels, especially depletion of complement
factors 2 and 4, may indicate deficiency of C1-inhibitor. HAE type III is a
diagnosis of exclusion consisting of observed angioedema along with normal
C1 levels and function.
 Skin prick test( to identify the allergen)
Management

 The primary goal of medical treatment for angioedema is to reduce and

prevent swelling, as well as to reduce discomfort and complication.
 Alpha- and beta-adrenergic agonist agents (eg, epinephrine)(due to life threatening
airway obstruction)
 First-generation antihistamines (eg, diphenhydramine, chlorpheniramine,
cyproheptadine, hydroxyzine hydrochloride)
 Second-generation antihistamines (eg, cetirizine, desloratadine, fexofenadine,
levocetirizine, loratadine)
 Histamine H2 antagonists (eg, ranitidine, cimetidine)
 Leukotriene receptor antagonists (eg, montelukast, zafirlukast)
 Corticosteroids (eg, prednisone, methylprednisolone, prednisolone)
 Androgen derivatives (eg, danazol, oxandrolone), progesterone-based birth control
pills.
 Antifibrinolytic agents (eg, aminocaproic acid, tranexamic acid)
 Anaphylaxis diagnostic criteria.
Anaphylaxis is considered likely to be present if any 1 of the 3 following clinical
criteria is satisfied within minutes to hours:

 Acute symptoms involving skin, mucosal surface, or both, as well as at least

one of the following: respiratory compromise, hypotension, or end-organ
dysfunction

 Two or more of the following occur rapidly after exposure to a likely

allergen: hypotension, respiratory compromise, persistent gastrointestinal
symptoms, or involvement of skin or mucosal surface

 Hypotension develops after exposure to an allergen known to cause

symptoms for that patient: age-specific low blood pressure or decline of
systolic blood pressure of more than 30% compared to baseline