Overview
Definition:
Urticaria (hives) are transient, pruritic, erythematous, edematous wheals, while angioedema is a deeper swelling of the dermis, subcutaneous tissues, or submucosal tissues
Both can be caused by mast cell degranulation
C1 esterase inhibitor (C1-INH) deficiency is a critical, though less common, cause of recurrent angioedema, distinct from histamine-mediated urticaria and angioedema.
Epidemiology:
Hereditary Angioedema (HAE) affects approximately 1 in 10,000 to 1 in 50,000 individuals worldwide
It is inherited in an autosomal dominant pattern
Acquired Angioedema (AAE) is rarer and typically associated with lymphoproliferative disorders or autoimmune conditions.
Clinical Significance:
Prompt identification and management of C1-INH deficiency are crucial as it can lead to life-threatening airway compromise
Distinguishing it from allergic urticaria/angioedema is vital for appropriate treatment and preventing unnecessary use of antihistamines or corticosteroids, which are ineffective for C1-INH deficiency.
Clinical Presentation
Symptoms:
Recurrent, non-pruritic, non-erythematous, non-pitting edema
Swelling typically develops gradually over hours and can last for 2-5 days
Common sites include extremities, face, genitalia, gastrointestinal tract (abdominal pain, nausea, vomiting, diarrhea), and importantly, the larynx (dyspnea, stridor, dysphagia)
Urticaria may or may not be present concurrently
Family history of similar episodes is a key clue.
Signs:
Edema is often asymmetric and non-pitting
Vital signs may be normal unless airway compromise is present (tachycardia, tachypnea, stridor)
While urticaria may be present, the angioedema itself is usually not associated with urticarial wheals.
Diagnostic Criteria:
There are no universally agreed-upon specific diagnostic criteria for HAE, but a strong clinical suspicion based on recurrent angioedema, absence of urticaria, and a positive family history prompts investigation
For AAE, the presence of angioedema in the context of an underlying lymphoproliferative or autoimmune disease is suggestive.
Diagnostic Approach
History Taking:
Detailed history of recurrent swelling episodes: triggers (minor trauma, stress, dental procedures, infections), duration, location, associated symptoms (abdominal pain, dysphagia), presence of urticaria (often absent in HAE), and family history of angioedema or sudden deaths
Inquire about medications and any known autoimmune or hematologic conditions for AAE.
Physical Examination:
Assess for edema, noting its location, extent, and pitting nature
Crucially, examine the airway for signs of obstruction: stridor, hoarseness, or respiratory distress
Look for any accompanying urticarial lesions
A thorough abdominal examination for tenderness or distension is important
Evaluate for signs of underlying malignancy or autoimmune disease if AAE is suspected.
Investigations:
For suspected HAE: Initial screening involves measuring serum C4 levels (often low) and C1-INH functional assay and antigenic levels
Normal or low C4 is seen in HAE, whereas it is typically normal in allergic angioedema
Specific tests for HAE types: HAE-C1-INH (Type I & II) show reduced C1-INH function and antigen levels
HAE-FXII (Type III) has normal C1-INH levels
For suspected AAE: C1-INH functional assay is typically reduced, but antigenic levels may be normal or elevated, often with low C1q and low or normal C4
Autoimmune workup (ANA, cryoglobulins) and investigations for lymphoproliferative disorders may be needed.
Differential Diagnosis:
Allergic angioedema (IgE mediated, usually with urticaria and pruritus, responds to antihistamines/steroids)
ACE inhibitor-induced angioedema (non-histaminergic, can occur months to years after starting ACE-I, gradual onset)
Idiopathic angioedema (no identifiable cause)
Mast cell activation syndrome (can present with angioedema but often with other mast cell symptoms)
Food allergy-induced angioedema.
Management
Initial Management:
Airway management is paramount for laryngeal angioedema
For patients with suspected HAE or AAE and airway involvement, prompt referral to an emergency department is essential
Avoid triggers if known
Do NOT administer H1-antihistamines, corticosteroids, or epinephrine, as they are ineffective and can delay definitive treatment.
Medical Management:
Acute attacks: For HAE, treatment includes C1-INH concentrate (e.g., Berinert, Cinryze), icatibant (a bradykinin B2 receptor antagonist), or fresh frozen plasma (FFP) if other treatments are unavailable
For AAE, treatment targets the underlying condition, and C1-INH concentrate or icatibant can be used for acute attacks
Prophylaxis: Long-term prophylaxis for HAE may include C1-INH concentrate, lanadelumab (a monoclonal antibody targeting kallikrein), or attenuated androgens (e.g., danazol), though androgens are used cautiously in children due to side effects
For AAE, managing the underlying disease is primary
prophylactic treatments are similar to HAE if indicated.
Surgical Management:
Surgical intervention is generally avoided due to the risk of precipitating further, potentially life-threatening, angioedema
However, in severe cases of airway obstruction unresponsive to medical therapy, airway support (e.g., intubation, tracheostomy) may be necessary as a life-saving measure.
Supportive Care:
Close monitoring of respiratory status is crucial during acute episodes, especially with laryngeal involvement
Patient education on recognizing triggers, self-administration of medications (if prescribed), and when to seek emergency care is vital
Genetic counseling may be beneficial for families with HAE.
Complications
Early Complications:
Airway obstruction leading to asphyxiation (most critical)
Gastrointestinal complications including severe abdominal pain, bowel obstruction, or ischemia
Musculoskeletal complications (rare) including joint swelling and pain.
Late Complications:
Chronic morbidity due to frequent attacks, including psychological distress, impact on quality of life, and recurrent abdominal pain
Potential for damage to organs involved in the pathogenesis of AAE (e.g., kidneys in some autoimmune conditions).
Prevention Strategies:
For HAE: prophylactic medications and avoiding known triggers
For AAE: effective management of the underlying disease
Educating patients to carry emergency medication and an alert bracelet is important.
Prognosis
Factors Affecting Prognosis:
Timely diagnosis and initiation of appropriate treatment, particularly for airway edema
Availability of effective treatments for acute attacks and prophylaxis
Presence and severity of underlying condition in AAE.
Outcomes:
With modern treatments, the prognosis for HAE has significantly improved, with a substantial reduction in attack frequency and severity, and a marked decrease in mortality from airway obstruction
Patients can lead near-normal lives
Prognosis for AAE depends heavily on the underlying cause.
Follow Up:
Regular follow-up with an allergist/immunologist or hematologist specializing in angioedema is recommended
Monitoring for disease activity, treatment adherence, and potential long-term side effects of medications is essential
Annual review of laboratory markers (C4, C1-INH levels) may be indicated.
Key Points
Exam Focus:
Distinguish histamine-mediated urticaria/angioedema from bradykinin-mediated angioedema (HAE/AAE)
HAE/AAE are typically non-pruritic, non-erythematous, non-pitting, and don't respond to antihistamines/steroids/epinephrine
Low C4 and C1-INH functional levels are key markers for HAE
Airway involvement is the most life-threatening complication.
Clinical Pearls:
Always consider C1-INH deficiency in recurrent angioedema without clear allergic triggers, especially if family history is positive or if the swelling is not pruritic/erythematous
Early recognition of airway compromise is paramount
Have acute treatment options readily available for patients with diagnosed HAE/AAE.
Common Mistakes:
Treating suspected C1-INH deficiency angioedema with antihistamines or corticosteroids, which delays appropriate management and can worsen outcomes
Misinterpreting normal C4 levels in the presence of angioedema as ruling out HAE (especially HAE-FXII)
Failure to inquire about a family history of angioedema or unexplained deaths.