Angioedema Pathophysiology

By Dr Ananya Mandal, MD

Angioedema is basically swelling of the deeper layers of the skin. This is due to accumulation of fluids caused by an allergic reaction.

Pathogenesis of the types of angioedema has been studied extensively.

Allergic or Immunoglobin-E–Mediated Angioedema

In this type of angioedema the immunoglobulin E or IgE is the main mediator. The identified allergen or trigger (foods like peanuts, nuts, shellfish etc. or drugs like Angiotensin converting enzyme [ACE] inhibitors) triggers a Type 1 hypersensitivity reaction.

The trigger binds to the IgE and in turn activates mast cells. These mast cells then release histamine and other chemical mediators of inflammation.

The symptoms may begin anytime between a few minutes to an hour after exposure to the allergen.

Hereditary Angioedema

This is an inherited condition that runs in the family. This condition is of autosomal dominant inheritance. These attacks are usually episodic and hands and feet are commonly affected.

There is rare concomitant occurrence of urticaria. Symptoms usually begin during childhood but can start at any age.

Evidence shows that there is a C1 esterase inhibitor (C1 INH) deficiency. Normally C1 INH is responsible for regulation of activity of inflammatory mediators like complement component C1. Activation of C1 is the first step in the activation of complements and their role in inflammation.

In addition to complement activation the C1 INH also regulates the activation of the blood coagulation and fibrinolytic pathways that deal with blood clotting in response to inflammation.

If there is a deficiency of C1 INH the mediators of inflammation like bradykinin, kallikrein, and plasmin become overtly active.

  • Among 85% of patients with hereditary angioedema there is a defect in the gene that expresses C1 INH. This is seen in type 1 hereditary angioedema.
  • In Type 2 the blood levels of C1 INH is normal but this protein does not function normally.
  • In Type 3 there is a mutation in coagulation factor XII and this leads to increased production of kinin. This type is also called estrogen-dependent type because female hormone estrogen containing medications are seen to increase the symptoms.

Acquired Angioedema

Acquired angioedema also results due to C1 INH deficiency. There are 2 types of acquired angioedema and both have autoimmune mechanisms in their pathology.

Type 1 is associated with lymphoproliferative diseases like monoclonal gammopathy and lymphomas. In this type the cancer cells consume the C1 INH protein leading to their deficiency.

In Type 2 there is an autoantibody to the C1 INH protein that causes its depletion.

Drug induced Angioedema

Angiotensin-Converting Enzyme Inhibitors or ACE inhibitors are one of the common drugs that cause angioedemas. This results mainly due to raised levels of bradykinins.

Commonly affected sites include tongue, lips, and face and African Americans are 4 to 5 times more likely to be affected than whites.

Angioedemas due to physical stimuli

Some physical stimuli including cold, heat, emotional stress, ultraviolet light, trauma or vibration may also cause angioedema in some individuals.

In these conditions there is a raised level of several cytokines. There is an increased level of the cytokines granulocyte-macrophage colony-stimulating factor, interleukin (IL)-3, IL-5, and IL-6.

Reviewed by April Cashin-Garbutt, BA Hons (Cantab)

Sources

  1. http://pds25.egloos.com/pds/201301/04/64/The_Spectrum_and_Treatment_of_Angioedema.pdf
  2. http://www.clinicalmolecularallergy.com/content/6/1/2
  3. http://www.jiaci.org/issues/vol21issue5/1.pdf
  4. http://www.nhs.uk/conditions/Angioedema/Pages/Introduction.aspx
  5. http://www.acoi.org/StarrPass/Craig.pdf
  6. http://www.utmb.edu/otoref/grnds/angioedema-2012-0425/angioedema-pics-2012-0425.pdf
  7. http://www.adr.org.uk/factsheets/angioedema.pdf
  8. http://www.aaaai.org/Aaaai/media/MediaLibrary/PDF%20Documents/Practice%20and%20Parameters/urticaria_prt1-(1).pdf

Further Reading

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