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Angioedema

Disease Details

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Description: Angioedema is a medical condition characterized by rapid swelling of the deeper layers of the skin and tissues, often affecting the face, throat, and extremities.
Type: Angioedema can be broadly categorized into hereditary and acquired types.

Hereditary Angioedema (HAE) is primarily associated with genetic transmission and generally follows an autosomal dominant pattern. This means a mutation in just one copy of the responsible gene (often the C1 inhibitor gene, SERPING1) can cause the disorder.
Signs And Symptoms: The skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the tongue, swell over the period of minutes to hours. The swelling can also occur elsewhere, typically in the hands. The swelling can be itchy or painful. There may also be slightly decreased sensation in the affected areas due to compression of the nerves. Urticaria (hives) may develop simultaneously.
In severe cases, stridor of the airway occurs, with gasping or wheezy inspiratory breath sounds and decreasing oxygen levels. Tracheal intubation is required in these situations to prevent respiratory arrest and risk of death.
Sometimes, the cause is recent exposure to an allergen (e.g. peanuts), but more often it is either idiopathic (unknown) or only weakly correlated to allergen exposure.
In hereditary angioedema (HAE), often no direct cause is identifiable, although mild trauma, including dental work and other stimuli, can cause attacks. There is usually no associated itch or urticaria, as it is not an allergic response. Patients with HAE can also have recurrent episodes (often called "attacks") of abdominal pain, usually accompanied by intense vomiting, weakness, and in some cases, watery diarrhea, and an unraised, nonitchy splotchy/swirly rash. These stomach attacks can last one to five days on average and can require hospitalization for aggressive pain management and hydration. Abdominal attacks have also been known to cause a significant increase in the patient's white blood cell count, usually in the vicinity of 13,000 to 30,000. As the symptoms begin to diminish, the white count slowly begins to decrease, returning to normal when the attack subsides. As the symptoms and diagnostic tests are almost indistinguishable from an acute abdomen (e.g. perforated appendicitis) it is possible for undiagnosed HAE patients to undergo laparotomy (operations on the abdomen) or laparoscopy (keyhole surgery) that turns out to have been unnecessary.
HAE may also cause swelling in a variety of other locations, most commonly the limbs, genitals, neck, throat and face. The pain associated with these swellings varies from mildly uncomfortable to agonizing pain, depending on its location and severity. Predicting where and when the next episode of edema will occur is impossible. Most patients have an average of one episode per month, but there are also patients who have weekly episodes or only one or two episodes per year. The triggers can vary and include infections, minor injuries, mechanical irritation, operations or stress. In most cases, edema develops over a period of 12–36 hours and then subsides within 2–5 days.
Prognosis: The prognosis for angioedema largely depends on its underlying cause and severity. In cases where the trigger is identified and managed, such as avoiding allergens or discontinuing certain medications, the prognosis is generally good. However, recurrent episodes can occur, especially in hereditary angioedema, which may require long-term treatment and careful management. Severe cases involving the airways can be life-threatening and require immediate medical attention. The responsiveness to treatment and the ability to prevent future episodes are key factors in determining the overall prognosis.
Onset: Angioedema typically has a rapid onset, occurring over minutes to hours. The non-allergic form can be triggered by factors like medications (e.g., ACE inhibitors), physical stimuli, or can be hereditary.
Prevalence: The prevalence of angioedema can vary based on its type and underlying causes.

- **Hereditary Angioedema (HAE)**: This rare type occurs in about 1 in 50,000 to 1 in 150,000 individuals.
- **Acquired Angioedema (AAE)**: This is also rare, often associated with conditions like lymphoproliferative disorders.
- **Drug-Induced Angioedema**: Especially common with ACE inhibitors, affecting 0.1-0.7% of users.
- **Idiopathic Angioedema**: The prevalence is not well-documented but is assumed to be higher than the hereditary and acquired types.

Overall, specific prevalence rates are challenging to pinpoint due to varying factors including type, region, and population studied.
Epidemiology: In the U.S., there are as many as 80,000 to 112,000 emergency department (ED) visits for angioedema annually, and it ranks as the top allergic disorder resulting in hospitalization.
Intractability: Angioedema is typically not considered intractable, as many cases can be managed effectively with appropriate treatment and avoidance of triggers. However, recurrent or chronic angioedema can be challenging to control and may require ongoing management, including medications such as antihistamines, corticosteroids, or specific therapies like C1 inhibitor concentrates for hereditary forms.
Disease Severity: Angioedema severity can vary:
- Mild to moderate cases typically involve isolated swelling without additional complications.
- Severe cases may involve extensive swelling that impacts the airways, potentially resulting in life-threatening breathing difficulties.
Prompt medical attention is crucial, especially if the swelling impacts breathing or is accompanied by other symptoms like hives or abdominal pain.
Healthcare Professionals: Disease Ontology ID - DOID:1558
Pathophysiology: Bradykinin plays a critical role in all forms of hereditary angioedema. This peptide is a potent vasodilator and increases vascular permeability, leading to rapid accumulation of fluid in the interstitium. This is most obvious in the face, where the skin has relatively little supporting connective tissue, and edema develops easily. Bradykinin is released by various cell types in response to numerous different stimuli; it is also a pain mediator. Dampening or inhibiting bradykinin has been shown to relieve HAE symptoms.
Various mechanisms that interfere with bradykinin production or degradation can lead to angioedema. ACE inhibitors block ACE, the enzyme that among other actions, degrades bradykinin. In hereditary angioedema, bradykinin formation is caused by continuous activation of the complement system due to a deficiency in one of its prime inhibitors, C1-esterase (aka: C1-inhibitor or C1INH), and continuous production of kallikrein, another process inhibited by C1INH. This serine protease inhibitor (serpin) normally inhibits the association of C1r and C1s with C1q to prevent the formation of the C1-complex, which
Carrier Status: Carrier status for angioedema involves genetic mutations that can be inherited. There are two main types of hereditary angioedema (HAE):

1. **Type I and Type II HAE:** These are caused by mutations in the SERPING1 gene, which leads to deficient or dysfunctional C1 inhibitor protein. Individuals with one mutated copy of the SERPING1 gene are generally carriers and may experience mild symptoms or be asymptomatic, while those with two mutated copies display more severe symptoms.

2. **HAE with normal C1-INH function (Type III):** This type is less understood but is often associated with genetic mutations, such as those in the F12 gene. Carriers might not show symptoms, but they can pass the mutation on to their offspring.

In both cases, carriers have a 50% chance of passing the mutated gene to their children, who may develop the condition if they inherit the gene.
Mechanism: Angioedema is a condition characterized by rapid swelling of the deeper layers of the skin and mucous membranes. The mechanism involves increased permeability of blood vessels, leading to fluid leakage into the interstitial tissues.

**Molecular Mechanisms:**

1. **Bradykinin-Mediated Angioedema:**
- This type involves excessive production or impaired degradation of bradykinin, a peptide that increases vascular permeability.
- Hereditary Angioedema (HAE) is commonly associated with mutations in the SERPING1 gene, leading to deficient or dysfunctional C1 inhibitor protein, which normally regulates bradykinin production.
- Acquired forms may result from conditions that reduce C1 inhibitor levels or function.
- Certain medications like ACE inhibitors can increase bradykinin levels by inhibiting its breakdown.

2. **Histamine-Mediated Angioedema:**
- Often related to allergic reactions and involves the release of histamine and other mediators from mast cells and basophils.
- Triggers include allergens, physical stimuli (e.g., pressure, temperature), and certain medications.

3. **Complement System Activation:**
- Part of the immune response, the complement system can be activated inappropriately in conditions like HAE, leading to increased bradykinin and subsequent vascular permeability.
- Activation of the classic pathway due to antibody-antigen complexes or the alternative pathway can also contribute to vessel permeability changes.

Understanding these molecular mechanisms can aid in the accurate diagnosis and targeted treatment of angioedema.
Treatment: Angioedema treatment focuses on relieving symptoms and preventing future episodes.

1. **Acute Management**:
- Antihistamines (e.g., diphenhydramine) to reduce swelling and itching.
- Corticosteroids (e.g., prednisone) to reduce inflammation.
- Epinephrine for severe or life-threatening cases, such as those involving airway obstruction.

2. **Prevention and Long-term Management**:
- Avoid known triggers (e.g., certain foods, medications).
- For hereditary angioedema (HAE), treatments may include C1 esterase inhibitor concentrates, bradykinin receptor antagonists (e.g., icatibant), or kallikrein inhibitors (e.g., ecallantide).
- Regular use of prophylactic medications in chronic cases.

3. **Other Supportive Measures**:
- Maintain airway patency in severe cases.
- Close monitoring in a hospital setting if necessary.
Compassionate Use Treatment: Angioedema is a rapid swelling beneath the skin or mucosa, often due to an allergic reaction. For patients who do not respond to standard treatments, several options may be considered under compassionate use or off-label:

1. **Icatibant**: A bradykinin B2 receptor antagonist often used off-label for hereditary angioedema (HAE) attacks. It can also be considered for certain cases of non-hereditary angioedema.

2. **Ecallantide**: A kallikrein inhibitor approved for HAE but may be used off-label in some types of angioedema.

3. **C1 Inhibitor Concentrates**: Used for HAE, off-label use includes other forms of angioedema not responsive to conventional treatments.

4. **Rituximab**: A monoclonal antibody usually reserved for refractory cases, particularly those secondary to autoimmune conditions.

5. **Omalizumab**: Originally for allergic asthma and chronic urticaria, it is sometimes employed off-label for chronic, idiopathic angioedema.

These treatments should be considered carefully, considering potential risks and benefits.
Lifestyle Recommendations: Lifestyle recommendations for managing angioedema include:

1. **Avoid Triggers**: Identify and avoid known triggers such as certain foods, medications, insect stings, or stress.

2. **Manage Allergies**: Use hypoallergenic products and avoid allergens that may cause reactions.

3. **Medication Compliance**: Take prescribed medications as directed by your healthcare provider, including antihistamines or other treatments.

4. **Dietary Adjustments**: Follow any dietary restrictions to avoid foods that may trigger symptoms.

5. **Stress Management**: Practice stress-reducing techniques such as yoga, meditation, or deep-breathing exercises.

6. **Routine Monitoring**: Regularly monitor symptoms and seek medical advice if there are changes or worsening of the condition.

7. **Emergency Plan**: Have an emergency plan in place, including carrying an epinephrine auto-injector if recommended by a healthcare provider.

8. **Skin Care**: Use gentle skin care products to avoid irritation.

9. **Hydration**: Stay well-hydrated to maintain overall skin health.

10. **Medical Identification**: Wear a medical alert bracelet to inform others of your condition in case of an emergency.
Medication: For angioedema, treatment typically includes antihistamines like diphenhydramine, corticosteroids such as prednisone to reduce inflammation, and epinephrine in severe cases. If angioedema is caused by ACE inhibitors, stopping the medication is crucial. For hereditary angioedema, C1 esterase inhibitor concentrates or bradykinin receptor antagonists like icatibant may be used. Prompt medical attention is essential.
Repurposable Drugs: Repurposable drugs for angioedema include:

1. **Icatibant (Firazyr)**: Originally developed for hereditary angioedema (HAE), it is a bradykinin B2 receptor antagonist.
2. **Ecallantide (Kalbitor)**: Initially for HAE, it is a kallikrein inhibitor.
3. **C1 Esterase Inhibitor**: Used for HAE, it can be human-derived (Berinert, Cinryze) or recombinant (Ruconest).
Metabolites: Angioedema involves swelling of the deeper layers of the skin, often caused by an allergic reaction. The most relevant metabolites in angioedema are bradykinin and histamine. Bradykinin is typically involved in non-allergic angioedema (e.g., hereditary angioedema), while histamine plays a key role in allergic or histamine-mediated angioedema.
Nutraceuticals: There are no well-established nutraceuticals specifically proven to treat angioedema effectively. Management often involves identifying and avoiding triggers, and treating symptoms with medications such as antihistamines, corticosteroids, or epinephrine in severe cases. Patients should consult healthcare providers for personalized recommendations.
Peptides: Angioedema is a condition characterized by rapid swelling of the deeper layers of the skin and mucous membranes. Various peptides, such as bradykinin, play a critical role in its pathophysiology. Elevated levels of bradykinin, often due to genetic deficiencies in C1 esterase inhibitor (inherited angioedema) or as a side effect of medications like ACE inhibitors, can lead to increased vascular permeability and subsequent swelling. The term "nan" might not be directly relevant to angioedema unless it pertains to a specific context not provided.