Angioedema: Symptoms, Types, Causes and Treatment

Angioedema is a potentially serious condition characterized by sudden swelling beneath the skin or mucous membranes. While it can be frightening, understanding its symptoms, types, causes, and available treatments can help patients and healthcare providers respond effectively. This article synthesizes the latest research to provide a thorough, human-centered guide to angioedema.

Symptoms of Angioedema

Angioedema presents with a distinctive set of symptoms that often develop rapidly. Recognizing these symptoms early is crucial, as some forms—especially those affecting the airway—can be life-threatening. Swelling typically affects the skin or mucosa, but the exact pattern varies depending on the underlying type of angioedema.

Symptom	Description	Risk Level	Source(s)
Skin Swelling	Localized swelling of face, extremities, genitals, or trunk	Usually mild/moderate, but can be disfiguring	1, 2, 3, 5, 6, 8, 10, 11
Abdominal Pain	Severe, cramping pain due to bowel wall swelling	Can mimic acute abdomen, may cause vomiting	1, 2, 5, 11
Airway Involvement	Swelling of tongue, larynx, or soft palate	Life-threatening due to risk of asphyxia	1, 2, 3, 4, 5, 11, 14
Absence of Urticaria	Swelling without accompanying hives (wheals)	Helps differentiate from allergic reactions	6, 8, 10, 19

Table 1: Key Symptoms

Swelling Patterns and Locations

• Skin Swelling: The most common symptom. Areas affected include the face, hands, feet, and sometimes the genitals or trunk. Swellings are usually non-pitting, non-itchy, and persist for several hours to days 1, 2, 3, 11.
• Abdominal Attacks: Angioedema can cause the lining of the gut to swell, resulting in severe abdominal pain, vomiting, and sometimes diarrhea. These attacks are common in hereditary forms and may be mistaken for surgical emergencies 1, 2, 5, 11.
• Airway Involvement: Edema of the tongue, throat, or larynx is less common but extremely dangerous, posing a risk of airway obstruction and asphyxiation. Early symptoms may include hoarseness, difficulty swallowing, or a sensation of throat tightness 1, 2, 3, 4, 5, 14.
• Other Sites: Rarely, swelling may affect the urinary bladder, chest, muscles, joints, kidneys, or esophagus 1.

Symptom Evolution and Triggers

• Swelling typically develops over several hours and resolves within a few days 11.
• Attacks may be triggered by trauma, stress, infection, hormonal changes (such as oral contraceptives or pregnancy), or specific medications like ACE inhibitors 3, 4, 14.
• Unlike allergic angioedema, itching and urticaria (hives) are generally absent in bradykinin-mediated forms, which aids in distinguishing the two 6, 8, 10, 19.

Types of Angioedema

Angioedema is not a single disease but a clinical syndrome with multiple forms. Understanding the different types is essential for diagnosis and treatment.

Type	Key Features	Main Mediator	Source(s)
Hereditary (C1-INH Deficiency)	Recurrent swelling, family history, C1-INH dysfunction	Bradykinin	1, 5, 6, 10, 11, 12, 13
Hereditary (Normal C1-INH)	Swelling, often in women, normal C1-INH tests	Bradykinin	2, 3, 4, 7, 10
Acquired (C1-INH Deficiency)	Later onset, associated with malignancy or autoimmunity	Bradykinin	6, 8, 9, 17
ACE Inhibitor-Induced	Occurs after starting ACE inhibitors, no family history	Bradykinin	8, 9, 10, 14, 15
Allergic (Histaminergic)	Swelling with hives, responds to antihistamines	Histamine	6, 8, 9, 10, 17, 19
Idiopathic	Unknown cause—may be histaminergic or non-histaminergic	Histamine or Bradykinin	6, 8, 9, 10

Table 2: Types of Angioedema

Hereditary Angioedema (HAE)

• C1-INH Deficiency (Types I & II): Caused by mutations in the SERPING1 gene, resulting in low or nonfunctional C1 inhibitor. Presents in childhood or adolescence with recurrent, unpredictable swelling 1, 5, 6, 10, 11, 12, 13.
• Normal C1-INH (“Type III”/HAEnCI): Normal C1-INH levels and function, but with a similar clinical pattern. More common in women, often triggered or worsened by estrogens. Several gene mutations identified (e.g., factor XII, plasminogen, angiopoietin-1, kininogen-1) 2, 3, 4, 7, 10.

Acquired Angioedema

• C1-INH Deficiency: Usually develops in adulthood, often associated with underlying diseases like lymphoma or autoimmune disorders 6, 8, 9, 17.
• ACE Inhibitor-Induced: Bradykinin-mediated swelling that can develop any time after starting ACE inhibitors (e.g., for hypertension or heart failure). Swelling often affects the face, lips, tongue, or airway and may be severe 8, 9, 10, 14, 15.

Allergic and Idiopathic Angioedema

• Allergic (Histaminergic): Swelling with hives, often triggered by foods, drugs, or insect stings. Responds well to antihistamines, corticosteroids, or epinephrine 6, 8, 9, 10, 17, 19.
• Idiopathic: No identified cause. Some cases are histaminergic and responsive to antihistamines; others are non-histaminergic and more challenging to treat 6, 8, 9, 10.

Causes of Angioedema

The underlying causes of angioedema reflect its diverse forms. Pinpointing the cause is vital for selecting the right treatment.

Cause	Mechanism	Typical Age of Onset	Source(s)
C1-INH Deficiency	Genetic mutation → bradykinin excess	Childhood/Adolescence	1, 5, 12, 13
Factor XII/Other Mutations	Gene mutations affecting bradykinin regulation	Adolescence/Adulthood	2, 3, 4, 7
ACE Inhibitors	Drug blocks bradykinin breakdown	Any (after starting medication)	8, 9, 10, 14, 15
Allergens	IgE-mediated mast cell activation	Any	8, 9, 10, 17, 19
Autoimmunity/Malignancy	Acquired C1-INH deficiency	Older adults	6, 8, 9, 17
Unknown	Idiopathic mechanisms	Any	6, 8, 9, 10

Table 3: Causes of Angioedema

Genetic Causes

• Hereditary C1-INH Deficiency: Mutations in the SERPING1 gene cause insufficient or dysfunctional C1 inhibitor, a protein that normally controls bradykinin production. Unchecked bradykinin leads to leakage of plasma into surrounding tissues, causing swelling 1, 5, 12, 13.
• Other Genetic Mutations: Mutations in factor XII, plasminogen, angiopoietin-1, or kininogen-1 genes can disrupt bradykinin regulation, leading to HAE with normal C1-INH (HAEnCI) 2, 3, 4, 7.

Acquired and Drug-Induced Causes

• ACE Inhibitors: These common blood pressure medications inhibit bradykinin breakdown. In susceptible individuals, this can cause dangerous levels of bradykinin and sudden swelling, especially of the face and airway 8, 9, 10, 14, 15.
• Acquired C1-INH Deficiency: Can occur due to autoimmune processes (e.g., autoantibodies against C1-INH) or as a paraneoplastic syndrome (e.g., lymphoma) 6, 8, 9, 17.

Immune and Idiopathic Causes

• Allergic Reactions: Exposure to allergens can trigger the release of histamine from mast cells, leading to swelling. This type is usually accompanied by hives and responds to anti-allergy medications 8, 9, 10, 17, 19.
• Idiopathic Angioedema: In many cases, no clear trigger is found. Some cases are thought to be autoimmune or represent forms of chronic urticaria without hives 6, 8, 9, 10.

Treatment of Angioedema

Management of angioedema depends on its underlying cause, the severity of symptoms, and the risk of airway compromise. Rapid recognition and intervention can be lifesaving.

Treatment	Indication	Response	Source(s)
C1-INH Concentrate	Hereditary/Acquired C1-INH deficiency	Highly effective	5, 9, 16, 18
Icatibant	Bradykinin-mediated (including ACEi-induced)	Rapid symptom relief	9, 15, 16
Ecallantide	Acute HAE attacks	Effective	16, 9
Antihistamines, Steroids, Epinephrine	Allergic/histaminergic angioedema	Effective	8, 9, 17, 18, 19
Androgens (danazol, stanozolol)	Long-term HAE prophylaxis	Preventive	3, 17, 9
Tranexamic Acid	Prophylaxis (select cases)	Useful in some	3, 4, 9
Airway Management	Any severe/life-threatening swelling	Critical	5, 14, 18, 19

Table 4: Main Treatments

Acute Management

• Bradykinin-Mediated Angioedema: Standard allergy treatments (antihistamines, corticosteroids, epinephrine) are usually ineffective. Instead:

  • C1-INH Concentrate: Replacement therapy is the gold standard for hereditary or acquired C1-INH deficiency 5, 9, 16, 18.
  • Icatibant: A bradykinin B2 receptor antagonist, rapidly reverses symptoms in hereditary angioedema and ACE inhibitor-induced angioedema 9, 15, 16.
  • Ecallantide: A kallikrein inhibitor that prevents bradykinin formation, also effective for acute attacks 16, 9.
  • Airway Support: In cases of airway involvement, securing the airway (intubation or tracheostomy) is a top priority 5, 14, 18, 19.

• Histaminergic (Allergic) Angioedema: Responds well to antihistamines, corticosteroids, and, in anaphylaxis, epinephrine 8, 9, 17, 18, 19.

Long-Term Prophylaxis

• Androgens: Agents like danazol and stanozolol increase C1-INH production and can prevent HAE attacks but may have significant side effects 3, 17, 9.
• Tranexamic Acid: An antifibrinolytic agent that can be effective for some patients, especially those with HAE with normal C1-INH 3, 4, 9.
• Hormonal Management: Avoiding estrogen-containing medications is critical in women with estrogen-sensitive forms (e.g., HAE-FXII) 3, 4.

Patient Education and Monitoring

• Trigger Avoidance: Patients should be educated about avoiding known triggers such as trauma, certain medications (especially ACE inhibitors), and unnecessary surgeries 3, 5, 18.
• Emergency Plans: Those at risk for airway attacks should have an emergency action plan and access to on-demand treatments 5, 9, 19.
• Regular Follow-Up: Monitoring disease activity and treatment side effects is essential for optimal long-term care 5, 9, 18.

Conclusion

Angioedema is a complex, multifaceted condition that requires careful attention to detail for effective diagnosis and treatment. By understanding the distinct symptoms, types, causes, and management strategies, clinicians and patients alike can greatly improve outcomes and reduce the risk of life-threatening complications.

Key Points:

• Angioedema manifests as sudden, localized, and often recurrent swelling, sometimes threatening the airway.
• Major types include hereditary (with or without C1-INH deficiency), acquired, drug-induced (notably by ACE inhibitors), allergic, and idiopathic forms.
• Causes range from genetic mutations to medications and immune dysfunction, with bradykinin and histamine being key mediators.
• Treatment must be tailored to the underlying mechanism: bradykinin-mediated angioedema requires specific therapies, while allergic forms respond to antihistamines and steroids.
• Rapid recognition of airway involvement and prompt intervention are critical to prevent fatalities.

Armed with this comprehensive knowledge, patients and practitioners can work together to manage angioedema safely and effectively.