UNDERSTANDING HEREDITARY ANGIOEDEMA (HAE) AND ITS TREATMENT

Medically Reviewed by Dr. Sony Sherpa, (MBBS) - August 19, 2024

A rare genetic illness, Hereditary Angioedema (HAE) is characterized by repeated attacks of angioedema or extremely severe swelling in numerous body regions, including the face, lips, tongue, neck, abdomen, and limbs.

The swelling can be painful and sometimes life-threatening if it affects the airway. HAE affects about 1 in 50,000 people worldwide and does not depend on ethnicity or gender.

What is Hereditary Angioedema?

Angioedema is a general term for severe swelling of the skin, formerly referred to as angioneurotic edema^[1]. There are four types of angioedema, with HAE being one type. The others include allergic, drug-induced, and idiopathic (of unknown causes).^[2]

The majority of HAE subtypes are brought on by gene mutations that alter the synthesis or activity of a protein known as C1 inhibitor (C1INH). C1INH is involved in regulating the levels of bradykinin, a substance involved in blood clotting, inflammation, and wound repair that causes blood vessels to dilate^[3]. When C1INH is deficient or dysfunctional, bradykinin accumulates, causing excess fluid to leak from the blood vessels, which results in severe swelling or angioedema.

There are three main HAE types:^[4]

• Type I: This is the most common type, accounting for about 85% of cases. It is caused by low levels of C1INH in the blood.
• Type II: This accounts for about 15% of cases. It is caused by normal levels of C1INH but with reduced function.
• Type III: A rare type, affecting less than 1% of cases. It is often caused by mutations in another gene called F12, which encodes factor XII, a protein that activates bradykinin production. Type III mainly affects women and may be influenced by hormonal factors.

One copy of the mutant gene from each parent is enough to generate HAE because it is inherited in an autosomal dominant way. However, some people may have a new mutation that occurs spontaneously without a family history of HAE.

Symptoms of Hereditary Angioedema

HAE symptoms vary from person to person and even within the same person over time. They usually start in childhood or adolescence and tend to worsen after puberty. The frequency and severity of attacks also vary, ranging from once every few months to several times a week. An attack tends to resolve on its own between 2-4 days.^[5]

The most common sites of swelling and symptoms are described below.

• Face: Swelling of the face most commonly presents as sudden lip swelling, as well as swelling of the cheeks, eyes, nose, or ears. It can cause difficulty speaking, eating, or breathing.
• Throat: Swelling of the tongue, palate, uvula, or larynx can cause hoarseness, difficulty swallowing, or choking. This is the most serious HAE consequence and, if untreated, can be fatal.
• Abdomen: Swelling of the stomach, intestines, or other organs can cause abdominal pain, nausea, vomiting, diarrhea, or constipation.
• Limbs: Swelling of the hands, feet, arms, or legs can cause pain, stiffness, or reduced mobility.
• Genitals: Swelling of the genitals can cause pain, discomfort, or difficulty urinating.

How is HAE Different from Acquired Angioedema?^[6]

HAE looks almost identical to most forms of angioedema. Unlike allergic or drug-induced reactions, HAE attacks occur throughout life and do not cause itching, hives, or anaphylaxis. They also do not respond to anti-histamines or corticosteroids.

Hereditary Angioedema symptoms may also be confused with the following conditions:

Lymphedema: Angioedema symptoms may resemble those of primary lymphedema, which refers to severe swelling caused by the buildup of lymph fluid. This kind of swelling can take months to develop, although it can be difficult to tell the difference in acute cases. It is usually the result of a tumor or lymphoma.^[7]

Acquired C1 Esterase Inhibitor Deficiency: Like HAE, acquired deficiency of C1INH can lead to recurrent episodes of angioedema due to low levels of C1 inhibitor and bradykinin excess. Acquired C1INH deficiency occurs as a result of another condition later on in life and is not hereditary.^[8]

Hereditary Angioedema Triggers^[9]

Some common triggers for attacks include:

• Stress
• Infection
• Injury
• Surgery
• Dental work
• Hormonal changes
• Medications (especially angiotensin-converting enzyme inhibitors and estrogen-containing contraceptives or hormone replacement therapy)

Hereditary Angioedema Diagnosis and Testing

The diagnosis of HAE is based on the following criteria:^[10]

• A history of recurrent episodes of unexplained swelling that last for more than six hours and resolve spontaneously within a few days.
• A family history of similar symptoms or a confirmed genetic mutation in C1INH or F12 genes.
• Laboratory tests that measure blood levels and function of C1INH and complement proteins (C4 and C2). Low levels or function of C1INH and low levels of C4 are indicative of type I or II HAE. Normal levels and function of C1INH and C4, with high levels of factor XII are suggestive of type III HAE. Acquired angioedema and C1INH deficiency are suggested by low levels of both C1INH and C4.

A doctor may check for other causes, such as allergy or lymphatic blockages if there is no history or confirmation from lab tests.

How is HAE treated?

HAE treatment aims to prevent attacks from occurring and to treat them quickly when they do occur.

Those with the condition do not respond to usual steroids or anti-histamines, and require specialized medication and treatment, as discussed below.^[11]

Prophylaxis

This involves taking medications regularly to reduce the frequency and severity of attacks. The medications used for prophylaxis include:

• C1INH Replacement Therapy (such as Cinryze or Berinert): These are plasma-derived or recombinant forms of C1INH that are given intravenously or subcutaneously. They are effective and safe but may be expensive or unavailable in some countries.
• Androgenic Steroids (such as Danazol or Stanozolol): These increase the production of C1INH by the liver and are helpful for short-term prevention, such as just before a procedure. Long-term use or high doses are linked to adverse effects such as female masculinization, weight gain, acne, hair loss, and liver issues.

Over and above medication, those with hereditary angioedema ought to try to minimize attacks by reducing known triggers. This includes maintaining a strong immune system, leading a healthier lifestyle, and taking extra care to avoid injuries. It is important for those with HAE to consult with a doctor about how to manage attacks before surgery or dental procedures.

Acute Treatment

This involves taking medications as soon as possible after the onset of an attack to stop the swelling and relieve the symptoms. The medications used for acute treatment include:

• C1INH Replacement Therapy: These can be given intravenously or subcutaneously to replenish the deficient or dysfunctional C1INH and inhibit bradykinin production.
• Bradykinin Receptor Antagonist: These are synthetic peptides that block the action of bradykinin on the blood vessels and prevent fluid leakage and swelling. They are given subcutaneously and have a rapid onset of action.
• Kallikrein Inhibitor: These are proteins that inhibit the activity of kallikrein, an enzyme that converts kininogen to bradykinin. They are given intravenously and have a fast onset of action.

In addition to medications, people with HAE should also receive genetic counseling^[12] and education about their condition and its management. They should carry a medical alert card or bracelet that identifies their condition and the medications they need. It is crucial for them to have access to emergency care and a specialist center that can provide expert advice and support.

Outlook

With proper diagnosis and treatment, people with HAE can lead normal and productive lives. Those with the disease may still experience unpredictable attacks that can affect their daily activities, work, school, or travel plans. Living with a chronic ailment that could be fatal and calls for treatment from specialized facilities can also be stressful.

Those with HAE need ongoing support and care from family, friends, healthcare providers, and patient organizations. By remaining proactive and informed about their condition and its management, they can improve their outcomes and well-being.

Conclusion

Hereditary angioedema is a rare genetic condition that makes one prone to non-allergic attacks of severe swelling. The symptoms begin in early childhood and are triggered by inflammatory factors that initiate blood clotting. Treatment demands avoiding known triggers, preparing for procedures with care, and taking medication that can help reduce the severity and frequency of attacks. While the swelling often goes away on its own, any attack can be potentially life-threatening. Those with HAE need access to an emergency medical facility capable of treating their condition, as well as ongoing support from friends, family, health initiatives, and healthcare providers. With access to the right treatment, those with HAE can potentially lead fulfilling lives with minimal risk.

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