Angioedema is defined as " subcutaneous tissues and/or submucosal tissues circumscribed non-pitting edema affecting lips, face, neck, and extremities oral cavity, larynx, and gut." It becomes life-threatening when it involves the larynx, while intestinal angioedema is painful and mimics acute abdomen.
Angioedema was first described in 1882 by Quincke, then by Osler in 1888 (hereditary angioedema), and finally in 1963 by Donaldson et al (the role of C1 inhibitor).
Classification of angioedema
Inherited (hereditary angioedema): Mutations in the gene encoding for C1-inhibitor cause hereditary angioedema and it is an autosomal dominant condition.
Acquired: lymphoproliferative disorders, autoimmune, neoplastic, infection and drug-induced.
A retrospective study showed angioedema was the second most common disorder after asthma for hospitalization in New York State. African Americans made up 42% of these angioedema admissions. Hereditary angioedema is a rare autosomal dominant condition and affects 1/50,000 individuals. A Swedish study showed hereditary angioedema affected females more severely compared to males.
In describing pathophysiology, angioedema is classified as histamine-mediated angioedema and bradykinin-mediated angioedema
Histamine-mediated angioedema is the most common and is secondary to mast-cells and basophil activation.
Bradykinin-mediated angioedema (hereditary angioedema, acquired C1-inhibitor deficiency and angiotensin-converting enzyme inhibitor-associated angioedema). Allergic reactions and hives do not trigger this condition. C1-inhibitor is a regulator of complement and the contact system; if deficient or dysfunctional it causes activation of the contact system resulting in uncontrolled production of kallikrein leading to proteolysis of high-molecular-weight kininogen and bradykinin, leading to edema by increasing in vascular permeability. Bradykinin-mediated angioedema is seen in:
C1 inhibitor is a serine protease inhibitor (SERPIN)  C1 inhibitor deficiency is associated with SERPING 1 mutation or mutated genes which encode for metabolizing and functioning enzymes of bradykinin. Abnormal accumulation of C1 inhibitor in dominant harmful disease affects plasma levels of hereditary angioedema type 1.
The presentation can be acute or chronic.
Symptoms can involve different systems including skin (Urticaria, flushing, pruritus), Respiratory (bronchospasm), GI symptoms (abdominal pain and vomiting). Onset is within 60 minutes of allergen exposure and may last for one to two days.
Etiologies: Drugs, foods, latex, and insect stings.
While comparing the bradykinin-mediated angioedema with histaminergic angioedema, the former has the following characteristics:
Acquired angioedema related to angiotensin-converting enzyme (ACE) inhibitor
Nonsteroidal anti-inflammatory disease-induced angioedema
NSAID induced drug reactions include angioedema presenting with urticaria and facial swelling.
Hereditary angioedema begins in childhood or young adulthood, gets worse at puberty and presents as recurrent episodes of swelling or abdominal pain. Patients can develop prominent prodromal symptoms like erythema marginatum (erythematous, serpentine,non-pruritic rash). An acute attack takes one day to peak and resolves in two to three days.
Acquired angioedema with C1 inhibitor deficiency
Acquired C1 inhibitor deficiency presents similarly to hereditary angioedema. However, the low C1 inhibitor in many cases is from an underlying lymphoproliferative disorder which increases protein consumption and an antibody against C1-INH causing overproduction of bradykinin.
Vital signs, level of consciousness, as well as a thorough ski, head, neck, respiratory and abdomen evaluation should be completed.
General monitoring of angioedema in the Emergency room include:
The initial evaluation in the Emergency room
A specific drug and family history is needed along with screening blood work for C4 for hereditary angioedema and tryptase for angioedema with anaphylaxis. These labs when drawn during acute attacks are useful during follow-ups. In the case of anaphylaxis, (tryptase is normal in hereditary angioedema one and two but will be elevated in cases of anaphylaxis and other mast cell disorders associated with angioedema). Flexible fiberoptic laryngoscopy may be done to evaluate the involvement of tongue and larynx in patients with head, neck and upper airway symptoms.
Clear differentiation between histamine-induced vs. bradykinin-induced angioedema can be life-saving.
Hereditary angioedema type 1: C1 inhibitor function low, C1-Inhibitor level low, and C4 level low
Hereditary angioedema type 2: C1 inhibitor function and C4 level will be low, but the C1 inhibitor level will be normal or high.
Confirm them by repeating the blood test.
Acquired C1-inhibitor deficiency: Low C1-inhibitor antigen and function and low C1q.
Treatment of Bradykinin-mediated angioedema is often resistant to standard therapies such as epinephrine, glucocorticoids or antihistamines.
Hereditary angioedema (On-demand treatment)
Pre-procedural (short-term) prophylaxis
C1 Inhibitor is the first-line long-term prophylaxis, while the androgens are used as second-line agents.
Hereditary angioedema with mutations in the F12 gene is treated as follows:
Acquired angioedema related to angiotensin-converting enzyme (ACE) inhibitor
Treatment is with antihistamines, epinephrine, and glucocorticoids. Care should be taken to stop the offending ACE inhibitor, and the patient should be not rechallenged with any of the ACE inhibitors in the future.
Acquired C1 inhibitor deficiency angioedema
Majority cases are asymptomatic and respond to immunochemotherapy Treatment of acute attacks with icatibant and plasma-derived C1 inhibitor concentrate, and prophylaxis is with rituximab with or without chemotherapy and splenectomy.
Angioedema is one of the differential diagnoses in sudden onset of diffuse isolated edema.
C1 inhibitor hereditary angioedema can be misdiagnosed as familial Mediterranean fever.
Histaminergic angioedema clinical course is 1 hour of allergen exposure, and it may last for one to two days.
Hereditary angioedema is a rare disease that often leads to delay in diagnosis as well as a misdiagnosis. Other factors leading to a misdiagnosis are unknown family history, gastrointestinal manifestations of disease without cutaneous involvement.
C1 inhibitor deficiency type 1 and 2 angioedema attacks are worse compared to acquired C1 inhibitor deficiency angioedema.
Patient education for Hereditary angioedema:
Proper training will comfort a patient's intimidating feeling of self-administration of Subcutaneous injections.
Train parents/caregivers with the following skills
It is important to follow-up closely during the first few months of treatment.
Encourage patients to keep a logbook for treatment compliance which should include document and report a breakthrough attack of hereditary angioedema.
Hereditary angioedema: the latest studies indicate that interference RNA mediated knockdown of F12 mRNA ( ALN-F12) is an approach for the prophylactic treatment of hereditary angioedema. Gene therapy in hereditary angioedema may provide an option of durable treatment, but requires further studies for safety and tolerability. Functional polymorphism KLKB1-428G/A with or without functional F12-46C/T polymorphisms may be helpful as prognostic markers of disease. One may monitor 6-keto-prostaglandin F1 alpha as it may be a risk assessment blood marker in ACE inhibitor-induced angioedema. Angioedema is best managed by an interprofessional team as it has very high morbidity and mortality. Patients should be referred to the appropriate specialist as soon as possible. Patients admitted with respiratory distress need ICU monitoring, and the anesthesia staff should be notified. A bedside tracheostomy set is highly recommended.
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