Angioedema

Waking up one morning to find your lips, eyelids, or even parts of your hands or feet, alarmingly swollen isn't just everyday puffiness; it could be angioedema, a condition characterised by sudden, dramatic swelling deeper under the skin compared to the more superficial hives (urticaria). While often benign and self-limiting, angioedema can sometimes be life-threatening, especially when it affects the throat or airways. 

Understanding this condition is crucial, not just for those who experience it, but also for their loved ones and healthcare providers, to ensure prompt recognition and appropriate management. This detailed guide aims to shed light on angioedema, from its underlying mechanisms to practical tips for living with the condition.

Angioedema is a medical condition characterised by rapid, significant swelling of the deeper layers of skin, as well as the tissues just beneath the skin (submucosal tissues). Unlike urticaria (hives), which affects the superficial layers of the skin and typically presents as itchy, raised red welts, angioedema causes diffuse, non-pitting swelling that can be painful or burning, but is usually not itchy. The swelling is a result of fluid leakage from blood vessels into the surrounding tissues, often triggered by a release of histamine, bradykinin, or other inflammatory mediators. 

Common areas affected include the face (especially the lips and eyelids), hands, feet, genitals, and internal organs such as the gastrointestinal tract, which can lead to severe abdominal pain, nausea, and vomiting. Crucially, swelling of the throat (larynx) or tongue can block the airways, leading to a life-threatening emergency.

Angioedema is not uncommon, though its exact prevalence can vary depending on the type. Acute angioedema, often linked to allergic reactions or medication use (like ACE inhibitors), is relatively widespread. Chronic angioedema, particularly chronic spontaneous angioedema (CSAE), affects approximately 0.1-0.2% of the general population. Hereditary angioedema (HAE), a rarer genetic form, is estimated to affect about 1 in 50,000 to 1 in 100,000 people worldwide. Acquired angioedema (AAE), another rare form, is typically seen in older adults and is associated with underlying autoimmune or lymphoproliferative disorders.

Angioedema isn't a single condition but rather a group of disorders categorised by their triggers and underlying mechanisms. Understanding the different types is key to accurate diagnosis and effective treatment.

Allergic Angioedema: This is the most common type, often occurring alongside urticaria. It's triggered by an allergic reaction, where the immune system releases histamine and other chemicals in response to an allergen. Common allergens include certain foods (e.g., peanuts, shellfish), insect stings, medications (e.g., penicillin), and latex. The swelling typically appears rapidly, within minutes to hours of exposure.
 

Drug-Induced Angioedema: This is classified into the following types. 

• ACE Inhibitor-Induced Angioedema: Angiotensin-converting enzyme (ACE) inhibitors, commonly prescribed for high blood pressure and heart failure, are a frequent cause. This type can occur at any time after starting the medication, even years later, and is not an allergic reaction but rather due to the accumulation of bradykinin. It can be severe, particularly affecting the airways.
• NSAID-Induced Angioedema: Non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen or aspirin can also trigger angioedema in some individuals, often through a non-allergic mechanism affecting prostaglandin pathways.

Hereditary Angioedema (HAE): This is a rare, genetic disorder caused by a deficiency or dysfunction of C1-esterase inhibitor (C1-INH), a protein that helps regulate certain immune and inflammatory pathways. HAE attacks can be spontaneous or triggered by minor trauma, stress, infections, or medical procedures. Swelling can affect the skin, gastrointestinal tract (leading to severe abdominal pain), and critically, the upper airways. There are three types of HAE:

• Type I HAE: Most common, characterised by low levels of functional C1-INH.
• Type II HAE: Normal levels of C1-INH but it doesn't function properly.
• HAE with normal C1-INH (HAEN): A newer category where C1-INH levels and function are normal, but other genetic mutations are suspected.

Acquired Angioedema (AAE): Also rare, AAE is similar to HAE in its mechanism (C1-INH deficiency) but is not genetic. It typically develops later in life and is often associated with underlying autoimmune diseases (e.g., lupus) or lymphoproliferative disorders (e.g., lymphoma), which consume or inactivate C1-INH.
 

Idiopathic Angioedema: When no clear cause can be identified despite thorough investigation, it's termed idiopathic angioedema. This type can be spontaneous or chronic, and while frustrating, management often focuses on controlling symptoms.

The underlying cause of angioedema often dictates its type and approach to treatment.

• Allergens: Specific foods (nuts, shellfish, eggs, milk), insect bites/stings, certain medications (antibiotics like penicillin, aspirin, NSAIDs), latex, and even pet dander can trigger an allergic reaction leading to angioedema.
• Medications: ACE inhibitors are a prominent cause, responsible for a significant number of angioedema cases. Other drugs like NSAIDs and even some oral contraceptives can also be implicated.
• Genetic Factors: Mutations in genes responsible for C1-esterase inhibitor are the direct cause of Hereditary Angioedema (HAE).
• Underlying Medical Conditions: Autoimmune diseases (e.g., lupus, certain lymphomas, monoclonal gammopathy of undetermined significance – MGUS) can lead to acquired angioedema by affecting C1-INH. Thyroid disorders can also sometimes be associated.
• Physical Stimuli: In some individuals, physical triggers like pressure, cold, heat, exercise, or even emotional stress can provoke angioedema episodes.
• Infections: Viral or bacterial infections can sometimes trigger angioedema, particularly in individuals with an underlying predisposition.
• Alcohol: While not a direct cause, alcohol consumption can sometimes exacerbate or trigger episodes in susceptible individuals.
• Idiopathic: In many cases, especially chronic spontaneous angioedema, no specific cause can be identified, and the condition is labelled idiopathic.

The hallmark symptom of angioedema is sudden, noticeable swelling. However, the exact presentation can vary:

• Localised Swelling: Most commonly affects the face (lips, eyelids, tongue), hands, feet, genitals, and throat. The swelling is often asymmetric.
• Skin Changes: The affected area may appear pale or normal in colour, unlike the redness often seen with hives. The skin feels taut and can be painful or have a burning sensation rather than being itchy.
• Gastrointestinal Symptoms: When the lining of the stomach or intestines swells, it can lead to severe abdominal pain, cramps, nausea, vomiting, and diarrhoea. These symptoms can sometimes be mistaken for an acute surgical emergency.
• Respiratory Symptoms: Swelling of the larynx (voice box) or pharynx (throat) can cause hoarseness, difficulty swallowing (dysphagia), noisy breathing (stridor), and a sensation of throat tightness. This is the most dangerous symptom, as it can quickly lead to airway obstruction and suffocation.
• Other Symptoms: Less commonly, swelling can occur in the bladder or other internal organs. Some individuals may experience fatigue or a general feeling of unwellness during an attack.

Diagnosing angioedema requires a careful medical history, physical examination, and often, specific laboratory tests.

Medical History: The doctor will ask about the onset, duration, frequency, and location of swelling episodes. They'll inquire about potential triggers (foods, medications, insect bites, stress), family history of swelling, and any associated symptoms like hives, abdominal pain, or breathing difficulties. A detailed medication review is crucial, especially regarding ACE inhibitors.

Physical Examination: The doctor will examine the swollen areas and assess for signs of airway compromise.

Blood Tests:

• C4 levels: A low C4 level is a strong indicator of C1-INH deficiency, suggesting hereditary angioedema (HAE) or acquired angioedema (AAE).
• C1-esterase inhibitor (C1-INH) quantitative and functional levels: These tests measure the amount and activity of the C1-INH protein. Low levels or impaired function confirm HAE Type I or Type II, respectively.
• C1q levels: This test helps differentiate between HAE and AAE. Low C1q levels are typically seen in AAE but are usually normal in HAE.
• Allergen-specific IgE tests (blood tests or skin prick tests): If allergic angioedema is suspected, these tests can help identify specific allergens.
• Other tests: Depending on the suspected underlying cause, other tests like antinuclear antibody (ANA) for autoimmune diseases or tests for lymphoproliferative disorders may be performed.

Exclusion of Other Conditions: The doctor will rule out other conditions that can cause swelling, such as cellulitis, deep vein thrombosis, or thyroid dysfunction.

Treatment for angioedema depends largely on the type and severity of the episode.

Acute Attack Treatment:

• Airway Management: For severe laryngeal angioedema, securing the airway is paramount. This may involve intubation (inserting a breathing tube) or a tracheostomy in extreme cases.
• Antihistamines and Corticosteroids: These are the first-line treatments for allergic angioedema and urticaria. However, they are generally ineffective for bradykinin-mediated angioedema (HAE, AAE, and ACE inhibitor-induced angioedema).
• Epinephrine (Adrenaline): For severe allergic angioedema with anaphylaxis symptoms, epinephrine is administered.
• C1-INH Concentrate: For HAE and AAE attacks, purified C1-INH concentrate (human plasma-derived or recombinant) can be administered intravenously to replace the deficient protein.
• Bradykinin B2 Receptor Antagonist (Icatibant): This drug blocks the action of bradykinin and is effective for acute HAE attacks. It can be given subcutaneously.
• Kallikrein Inhibitor (Ecallantide): This targets another pathway involved in bradykinin production and is used for acute HAE attacks.
• Fresh Frozen Plasma (FFP): In emergencies when specific HAE treatments are unavailable, FFP can provide C1-INH but carries risks of viral transmission and can sometimes worsen the attack due to additional bradykinin precursors.

Long-Term Management (Prophylaxis):

• Avoiding Triggers: Identifying and avoiding known triggers is crucial, especially for allergic angioedema and drug-induced types.
• Discontinuation of ACE Inhibitors: If angioedema is linked to ACE inhibitors, stopping the medication is essential.
• Androgens (for HAE): Attenuated androgens (e.g., Danazol) can increase C1-INH levels and are used for long-term prophylaxis in HAE, though they have side effects.
• Antifibrinolytics (for HAE): Tranexamic acid (Brands: Trenaxa, Pause) or aminocaproic acid can reduce the frequency of attacks by inhibiting fibrinolysis.
• C1-INH Concentrate (Prophylaxis): Regular infusions of C1-INH concentrate can prevent attacks in HAE patients.
• Novel Therapies for HAE: Newer drugs like Lanadelumab (a kallikrein inhibitor) and berotralstat (an oral kallikrein inhibitor) are available for long-term prophylaxis, offering more convenient and effective options.
• Management of Underlying Conditions: For AAE, treating the associated autoimmune or lymphoproliferative disorder is key.

• Family history of angioedema: Especially for hereditary forms.
• Use of ACE inhibitor medications: Common blood pressure drugs.
• History of allergies or allergic reactions: Increases risk for allergic angioedema.
• Co-occurring autoimmune diseases: Such as lupus for acquired angioedema.
• Lymphoproliferative disorders: Can lead to acquired angioedema.
• Chronic urticaria (hives): Often co-occurs with angioedema.
• Female gender: Some types, like HAEN, are more prevalent in women.
• Stress, infection, trauma, surgery: Can be triggers, especially for HAE.

• Airway obstruction: Life-threatening swelling of the throat or tongue.
• Severe abdominal pain and dehydration: From gastrointestinal swelling.
• Diagnostic delays: Leading to unnecessary procedures or prolonged suffering.
• Psychological impact: Anxiety, depression, and reduced quality of life.
• Medication side effects: From long-term prophylactic treatments.
• Recurrent attacks: Leading to chronic disability and absenteeism.

Living with angioedema can be challenging, but these tips can help you manage the condition and improve your quality of life:

• Develop an Action Plan: Work with your doctor to create a personalised action plan for managing attacks. This plan should include what to do during an emergency, when to seek medical attention, and contact information for your healthcare providers. Keep this plan accessible.
• Carry Emergency Medication: Always carry your prescribed emergency medications, such as an adrenaline auto-injector if you have allergic angioedema, or specific treatments for HAE. Ensure they are not expired and that you know how to administer them.
• Identify and Avoid Triggers: Keep a detailed diary of your attacks, noting potential triggers like foods, medications, stress levels, or activities. This can help you identify patterns and proactively avoid situations that might provoke an episode.

Misconception: Angioedema is always itchy like hives. 

Reality: While angioedema can sometimes occur with itchy hives, swelling itself is typically not itchy. Instead, it's often described as a burning, tingling, or painful sensation, or simply a feeling of tightness. This difference is key to distinguishing it from superficial urticaria.

Misconception: Angioedema is always an allergic reaction. 

Reality: Many people assume all angioedema is allergic, but this isn't true. While allergic reactions are a common cause, many types of angioedema, such as those caused by ACE inhibitors, hereditary angioedema, and acquired angioedema, are bradykinin-mediated and not allergic in nature.

Misconception: Angioedema is never serious. 

Reality: While many episodes of angioedema are benign and resolve on their own, swelling of the throat or tongue can be life-threatening if it obstructs the airways. Gastrointestinal swelling can also cause severe abdominal pain and dehydration, leading to emergency hospital visits.

You should see a doctor promptly if you experience any sudden, significant swelling, especially if:

• The swelling is rapidly worsening.
• It affects your lips, tongue, or throat, causing difficulty breathing, swallowing, or speaking (seek emergency medical help immediately).
• You experience severe abdominal pain, nausea, or vomiting along with swelling.
• The swelling is painful, burning, or lasts for an extended period.
• You have a known history of angioedema and are experiencing a new or more severe type of attack.
• You suspect your medication might be causing the swelling.

• What type of angioedema do I have, and what is its likely cause?
• What are the most effective treatment options for my specific type of angioedema?
• What emergency medications should I carry, and how should I use them?
• Are there any specific triggers I should try to avoid?
• What are the potential side effects of the recommended treatments?
• How can I best monitor my condition and know when to seek urgent medical attention?

• Understand their individual action plan for attacks, know where they keep emergency medications, and be ready to help administer them or call for emergency services if needed, especially if airway swelling occurs.
• If they are tracking their episodes, offer to help them identify potential triggers by noting down details of their diet, activities, stress levels, and medications around the time of an attack.
• Learn about their specific type of angioedema. Share accurate information with mutual friends, family, or colleagues to dispel myths and ensure they receive understanding and appropriate responses from others.

Angioedema, with its varied presentations and underlying causes, is a complex condition that can significantly impact a person's life. From the more common allergic and drug-induced forms to the rare hereditary and acquired types, understanding the specific mechanisms at play is crucial for effective diagnosis and management. While the sudden and often dramatic swelling can be alarming, particularly when it affects vital areas like the airways, advancements in treatment and a better understanding of triggers offer hope and improved quality of life.