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Hereditary Angioedema (HAE) – Causes and Treatment

Hereditary angioedema (HAE) is a rare, genetically inherited condition causing recurrent episodes of swelling in the skin, abdomen, and airways, which can be life-threatening.

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Things worth knowing about "Hereditary Angioedema"

Hereditary angioedema (HAE) is a rare, genetically inherited condition causing recurrent episodes of swelling in the skin, abdomen, and airways, which can be life-threatening.

What is Hereditary Angioedema?

Hereditary angioedema (HAE) is a rare, inherited disorder of the immune system characterized by recurrent episodes of severe swelling in various parts of the body. These swelling attacks are caused by an uncontrolled release of bradykinin, a vasoactive peptide that increases vascular permeability and leads to fluid leakage into surrounding tissues. HAE affects approximately 1 in 50,000 people and is inherited in an autosomal dominant pattern, meaning that a mutation in just one copy of the relevant gene is sufficient to cause the disease.

Causes

The most common cause of HAE is a deficiency or dysfunction of the C1-inhibitor (C1-INH) protein, which normally regulates the contact activation pathway of the blood. Three main types are distinguished:

HAE Type I: Reduced levels of C1-inhibitor in the blood (approximately 85% of cases).
HAE Type II: Normal or elevated C1-inhibitor levels but impaired protein function.
HAE with normal C1-inhibitor (formerly Type III): A rare form often associated with mutations in the Factor XII gene, predominantly affecting women.

Individual attacks can be triggered by stress, infections, trauma, surgery, hormonal changes (e.g., estrogen), or certain medications such as ACE inhibitors.

Symptoms

HAE-related swelling can affect virtually any part of the body and typically lasts 2 to 5 days. Common manifestations include:

Skin: Swelling of the hands, feet, face, and genitals – notably without itching, unlike allergic reactions.
Abdominal organs: Severe abdominal cramps, nausea, vomiting, and diarrhea due to swelling of the gastrointestinal tract wall.
Larynx (throat): Life-threatening swelling of the airways that can cause suffocation – this constitutes a medical emergency requiring immediate treatment.

Many patients experience a non-itchy, rash-like skin pattern called erythema marginatum as an early warning sign before an attack begins.

Diagnosis

Diagnosis of HAE is based on clinical evaluation, family history, and laboratory testing. Key diagnostic steps include:

Measurement of C1-inhibitor levels (both quantity and function) in the blood.
Assessment of the C4 complement factor, which is persistently low in HAE Types I and II.
Genetic testing to identify mutations in the SERPING1 gene (encoding C1-inhibitor) or the Factor XII gene.

Because HAE is rare and its symptoms can resemble other conditions (e.g., allergic angioedema, appendicitis), diagnosis is frequently delayed by years. Early investigation is especially important when there is a positive family history.

Treatment

Acute Attack Treatment

The following medications are used to treat acute HAE attacks:

C1-inhibitor concentrate (e.g., Berinert, Cinryze): Replaces the deficient protein, administered intravenously or subcutaneously.
Icatibant (Firazyr): A bradykinin B2 receptor antagonist administered as a subcutaneous injection, blocking the effects of bradykinin.
Ecallantid: A plasma kallikrein inhibitor (not approved in Europe).

Short-term Prophylaxis

Before planned surgical or dental procedures, preventive administration of C1-inhibitor concentrate or tranexamic acid can reduce the risk of an attack.

Long-term Prophylaxis

To prevent frequent attacks, the following options are available:

Lanadelumab (Takhzyro): A monoclonal antibody that inhibits plasma kallikrein, injected subcutaneously every 2 to 4 weeks.
Subcutaneous C1-inhibitor (Haegarda): Self-injected twice weekly.
Berotralstat (Orladeyo): An oral plasma kallikrein inhibitor taken once daily.
Older options include tranexamic acid and androgens (e.g., danazol), the latter now less commonly recommended due to significant side effects.

Quality of Life and Patient Management

HAE is a chronic condition that can significantly impact daily life. Patients should always carry an emergency medication kit and ensure that family members, colleagues, and healthcare providers are aware of their condition. Self-injection training enables many patients to treat attacks independently. Patient advocacy organizations such as the HAE International network provide valuable support and resources.

References

Maurer M. et al. - The international WAO/EAACI guideline for the management of hereditary angioedema - full update 2022. Allergy. 2022;77(7):1961-1990.
Farkas H. - Hereditary Angioedema: Classification and Current Management Options. Expert Review of Clinical Immunology. 2020.
Longhurst H., Cicardi M. - Hereditary angio-oedema. Lancet. 2012;379(9814):474-481.

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