Angioedema

How angioedema happens

In angioedema, chemical messengers make the walls of small blood vessels leaky. Fluid moves into the deep dermis, the fat beneath it, and the lining of the mouth, throat and bowel. Because these deeper layers have fewer itch nerves and more pain fibers than the surface, angioedema tends to burn or ache, whereas hives (swelling of the upper skin) itch.

Two different messengers cause it, and they respond to different treatments.

Histamine-mediated (mast cell) angioedema

Mast cells in the skin release histamine when triggered by an allergen or, in chronic urticaria, by autoantibodies or unknown factors. Swelling develops in minutes, often with itchy hives, and fades within 24 to 48 hours. Antihistamines, steroids and epinephrine work.

Bradykinin-mediated angioedema

Bradykinin is a peptide that dilates vessels. It builds up when its breakdown is blocked (by ACE inhibitors) or when its production is unchecked (in C1-inhibitor deficiency). Swelling develops more slowly, lasts 2 to 5 days, comes without hives, and does not respond to antihistamines, steroids or reliably to epinephrine.

Types of angioedema

ACE inhibitor angioedema

ACE inhibitors are among the most prescribed blood pressure medicines, so they cause a large share of emergency angioedema cases. Key facts:

• it affects a small fraction of users, more often Black patients, smokers and people with prior drug-related swelling
• it can start in the first week or after many years of uneventful use
• it often involves the tongue and throat and can need airway support
• the medicine must be stopped for good, and other ACE inhibitors avoided
• episodes can continue for weeks to months after stopping

ARBs are usually a reasonable alternative, but a small risk of recurrence exists, so doctors weigh this carefully.

Hereditary angioedema

Hereditary angioedema (HAE) is a rare inherited condition, affecting roughly 1 in 50,000 people, caused by low or faulty C1-inhibitor protein. Most cases are inherited in an autosomal dominant pattern, so each child of an affected parent has a 50% chance, but about a quarter arise from new mutations.

Features:

• swelling of the limbs, face, genitals and airway lasting 2 to 5 days
• severe abdominal pain attacks from bowel wall swelling, often mistaken for appendicitis
• a non-itchy, snake-like rash (erythema marginatum) before some attacks
• triggers include minor trauma, dental procedures, stress, infections and estrogen-containing pills or HRT
• laryngeal swelling can be fatal if untreated

Symptoms

• swelling of the lips, eyelids, tongue, cheeks, hands, feet or genitals
• burning, tight or painful skin
• hoarseness, throat tightness, difficulty swallowing
• cramping abdominal pain, nausea, vomiting, diarrhea
• hives in histamine-type angioedema

See angioedema symptoms for a practical guide to what to do during a swelling episode.

Diagnosis

Diagnosis is mostly based on history:

• What did you eat, take or touch beforehand?
• Did hives come with it?
• How long did it last, and did antihistamines help?
• Are you taking an ACE inhibitor, NSAID or estrogen?
• Does anyone in the family have swelling attacks?

Tests depend on the suspected type:

• Allergy skin-prick or specific IgE blood tests for food, drug, latex or sting allergy
• Serum tryptase soon after a severe reaction to support anaphylaxis
• C4 level: low in nearly all HAE patients, a useful screening test
• C1-inhibitor level and function: confirm HAE types 1 and 2
• C1q level: low in acquired C1-inhibitor deficiency
• Genetic testing: for HAE with normal C1-inhibitor
• Blood count, thyroid tests and inflammatory markers in chronic urticaria

Treatment

Emergency airway care

Any angioedema involving the airway is treated in the emergency department. Teams may need to secure the airway with a breathing tube or surgical airway.

Histamine-mediated angioedema

• Epinephrine injection for anaphylaxis or throat involvement
• Non-sedating antihistamines (H1 blockers), often at higher-than-standard doses under medical supervision for chronic urticaria
• Short courses of steroids for severe flares
• Omalizumab injections for chronic spontaneous urticaria not controlled by antihistamines
• Avoid known triggers. People with severe allergy carry two epinephrine auto-injectors.

Bradykinin-mediated angioedema

• ACE inhibitor angioedema: stop the drug permanently and support the airway. Antihistamines and steroids are often given but are unlikely to help.
• HAE acute attacks: C1-inhibitor concentrate, icatibant (a bradykinin receptor blocker) or ecallantide, ideally given early. Many patients self-administer at home.
• HAE prevention: long-term preventive treatment such as lanadelumab, berotralstat or regular C1-inhibitor, plus short-term prophylaxis before dental work or surgery.
• Avoid estrogen-containing medicines and ACE inhibitors in HAE.

Complications

• airway obstruction and death if laryngeal swelling is not treated
• unnecessary abdominal surgery when bowel attacks are mistaken for appendicitis
• reduced quality of life, missed school and work in recurrent forms

Outlook

Allergic angioedema is controlled by avoiding triggers and having an emergency plan. Chronic urticaria with angioedema usually improves over 1 to 5 years. ACE inhibitor angioedema stops once the medicine is withdrawn, though episodes may occur for a few months. HAE is lifelong, but modern preventive treatments have made attacks far less frequent for most patients.

Frequently asked questions

What causes angioedema?

Allergic reactions to foods, medicines, stings and latex, and chronic urticaria cause histamine-type angioedema. ACE inhibitor blood pressure drugs and hereditary or acquired C1-inhibitor deficiency cause bradykinin-type angioedema. In many cases of recurrent swelling no specific cause is found.

What is the treatment for angioedema?

Allergic angioedema is treated with antihistamines, steroids and epinephrine for severe reactions. Bradykinin types need different treatment: stopping ACE inhibitors, and for hereditary angioedema, C1-inhibitor concentrate or icatibant during attacks plus preventive medicines.

What is the difference between angioedema and hives?

Hives are itchy, raised welts in the upper layer of the skin that fade within hours. Angioedema is deeper swelling of the skin and mucous membranes that burns more than it itches and lasts longer. They often occur together in allergic reactions.

Why don't antihistamines work for my angioedema?

If antihistamines do not help, the swelling may be caused by bradykinin rather than histamine. This happens with ACE inhibitors and hereditary or acquired C1-inhibitor deficiency. Ask your doctor about your medicines and about C4 and C1-inhibitor blood tests.

Is angioedema dangerous?

Most episodes are not, but swelling of the tongue, throat or voice box can block the airway and be life-threatening. Anyone with throat symptoms needs emergency care. People with recurrent episodes should have a written action plan.