Angioedema

What is Angioedema?

Angioedema refers to swelling of the deeper layers of the skin. This is due to accumulation of fluids caused by an allergic reaction. Angioedema most commonly affects the face, lips, eyes, hands, genitals and feet.

Causes and pathogenesis

Since this is an allergic condition, it is more often than not associated with exposure to a trigger or allergen.

Most people with angioedema may also have other allergic manifestations including hives or urticaria. Hives or urticaria are red and itchy rashes with welts and typical rash that appear over the skin.

Types of angioedema

Angioedema may classified into four basic types according to its cause:-

  • Angioedema caused due to allergies – this type of angioedema may be caused due to a food allergy or allergy to a food additive or color. This type of angioedema may occur along with an anaphylactic reaction.
  • Angioedema due to drugs – some drugs may also cause allergies leading to angioedema. One of the common examples includes high blood pressure medications like angiotensin-converting enzyme (ACE) inhibitors, hormonal contraceptives, pain relievers like non steroidal anti-inflammatory drugs (NSAIDs like aspirin, ibuprofen etc.). Angiedema with the use of medications occurs as a side effect.
  • Genetic causes of angioedema
  • Idiopathic angioedema when no cause can be identified.

Symptoms

The swelling is pale and non-itchy. Symptoms last for 1 or 2 days. If angioedema affecting the tongue or upper airway is rapid, there may be difficulty in breathing. This can be life-threatening.

If the condition affects the gastrointestinal tract, there may be severe pain that is often mistaken for appendicitis, diverticulitis or mesenteric ischemia.

The swelling is caused by an increase in capillary leakage. There is leakage of fluids from the smaller blood vessels called capillaries. This leakage occurs due to release of mediators and chemicals of inflammation.

Who suffers from angioedema?

Angioedema is quite a common condition. It may affect up to 10-20% of the population in their life time.

Allergies to foods and medications are the most common type of angioedema. Food related allergies for example affect about 5-8% of children and 1-2% of adults.

Similarly angioedema due to ACE inhibitors affect around 1-5% of people who take them.

Idiopathic angioedema that may be long lasting or chronic may affect 1 in 2,000 persons.

Hereditary angioedema affects between 1 in 10,000 and 1 in 50,000 people worldwide and is thus considered rare.

Diagnosis of angioedema

Diagnosing angioedema is mainly with the help of history of exposure to a trigger and presentation with typical clinical features.

Idiopathic angioedema is typically diagnosed when no known cause or exposure is found.

Treatment of angioedema

Angioedema usually gets better without treatment after a few days if the trigger or allergen is removed.

Anti-allergy medications like antihistamines and steroids can be used to relieve the swelling and hasten recovery. Drug-induced angioedema needs use of alternative medications.

Angioedema Diagnosis

Angioedema diagnosis more often than not depends on the history of recent exposure to a triggering agent and presentation with typical clinical symptoms.

There are some tests that may be prescribed to determine the type of angioedema according to cause.

Diagnosis based on symptoms

Diagnosis is based on the symptoms of angioedema. Symptoms of angioedema include:-

  • Swelling of the skin. Angioedema commonly affects the face, eyes, lips, genitalia, hands and feet. The swelling is caused by a collection of fluid in the deep layers of the skin. In some cases the throat and the gastrointestinal tract may also be involved.
  • The swelling is acute or sudden in onset and is more aggressively progressing and severe than nettle rash or hives. It commonly lasts one to three days. There is usually no itching but a slight prickling sensation.
  • The swollen areas may feel hot and inflamed.
  • If there is rapidly growing swelling inside the throat and the tongue, breathing may become difficult and the condition may become life-threatening requiring urgent medical attention.
  • Eye swelling and swelling of the conjunctive may affect vision significantly.
  • Those with genetic or hereditary angioedema may also have nausea, vomiting, diarrhea and abdominal pain.
  • If the genitalia and urinary tract is involved, there may be pain and difficulty in passing urine.

Diagnosis of different types of angioedema

The diagnosis of each type of angioedema according to its cause includes:-

  • Diagnosing allergic angioedema

    The first step in diagnosing an allergy is a detailed history of an exposure to a possible allergen or triggering agent. This could be foods like nuts, eggs, soy, shellfish etc. This could also be exposure to latex or other allergy triggering agents.

    Physical triggers like cold, exercise, heat, sweating, sun (or light) exposure, pressure are also enquired. There could be a history of exposure to infections such as respiratory virus, viral hepatitis, or infectious mononucleosis. Exposures to irritants are work environments and recent insect sting or bite is asked.

    Those who have an existing allergic disease for example hives or asthma are more likely to be affected. Exposure to medications also needs to be detailed in history while diagnosing allergic angioedema.

    Further tests include the skin prick test and blood tests. These are usually performed at an allergy or immunology clinic. The skin prick test involves tiny pricks to the skin with very small amount of the suspected allergen. If allergic the results show up as inflammatory red and raised reactions at the specific pricks. Blood tests check for inflammatory markers in blood.

  • Diagnosing drug induced angioedema

    Diagnosing this type of angioedema involves taking a detailed history of all the drugs consumed. This includes prescription, over-the-counter, alternative and herbal medicines as well. If withdrawal of the drug resolves the angioedema, the diagnosis of drug-induced angioedema is confirmed.

  • Diagnosing genetic angioedema

    This form of angioedema is commonly inherited. There is a positive history of someone in the family (parent, sibling or a blood relation from either parent’s side) who has this condition. Blood is checked for level of proteins that are regulated by the C1-INH gene. Low levels are indicative of genetic or hereditary angioedema.

  • Diagnosing idiopathic angioedema

    Idiopathic angioedema is diagnosed and confirmed when no other cause is found.

Angioedema Treatment

Angioedema is essentially an allergic phenomenon. Treatment is common for all types of angioedema when the condition is a medical emergency.

Emergency treatment of Angioedema applicable for all types

  • Airway maintenance

    When angioedema affects the throat and tongue and there is rapidly progressing swelling of the throat, there may be progressive narrowing of the airways leading to difficulty in breathing. The priority of management in these conditions is emergency opening up of the airways and maintenance of respiration.

  • Endotracheal intubation

    If there is compromise in breathing, an endotracheal tube is inserted into the trachea and it is connected to oxygen tubes. This secures airway. Intubation should be performed as soon as possible since excessive swelling of the larynx and back of throat makes intubation difficult. In these cases a hole or opening is made over the neck (on the trachea) to enable air to pass. This is called tracheostomy.

Treatment of allergic angioedema

  • In allergic angioedema the first treatment is avoidance and removal of the triggering agent or allergen as far as possible.
  • Medications like antihistamines and glucocorticoids are agents that reverse the inflammatory activities and reverse the symptoms of angioedema.
  • Swelling of the larynx and airways can be reduced by the use of Adrenaline or epinephrine. Adrenaline can be given as an injection or via an endotracheal tube. Antihistamines are agents that counteract the actions of histamine. Daily antihistamines may decrease the severity of symptoms. However these agents do not prevent recurrent attacks.

Treatment of hereditary angioedema

These patients are generally advised to avoid triggers such as Angiotensin converting enzyme inhibitors and contraceptives containing estrogen.

Treatment is usually with the use of plasma-derived C1 INH concentrate. This is being used with success in Europe and Canada. Plasma-derived C1 INH concentrate however is not approved by the Food and Drug Administration for use in the United States.

Typically fresh-frozen plasma, which contains C1 INH is found to be as effective as C1 INH concentrate and symptoms improve within 30 to 60 minutes of the infusion.

Attenuated androgens including danazol are also used to increase the production of C1 INH from the liver and this prevents attacks in hereditary angioedema.

Angioedema Pathophysiology

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.