On this page
Hereditary angioedema
HAE leads to unpredictable swelling attacks in various body parts, including the skin, gut, and airways. These attacks can be painful, disfiguring, and potentially life-threatening if they affect the throat. It is typically inherited within families.
Overview
Hereditary angioedema (HAE) is a rare inherited condition characterised by sudden, recurrent episodes of swelling beneath the skin or mucous membranes. These attacks can affect many parts of the body, most commonly the limbs, face, gastrointestinal tract, and upper airways [PMID:33671216]. Unlike common allergies, HAE swelling does not typically itch and does not respond to antihistamines or adrenaline.
The condition affects approximately 1 in 50,000 people globally, though the exact prevalence in the UK is not precisely known. HAE is typically diagnosed after repeated swelling episodes, often with a family history of similar symptoms. Early and accurate diagnosis is important for effective management and to prevent potentially life-threatening airway swelling.
Symptoms & clinical features
HAE symptoms primarily involve episodes of oedema, which is severe swelling. These attacks often develop slowly over several hours and can last for two to five days if untreated. The severity and frequency of swelling episodes can vary greatly, even within the same family. Attacks can be triggered by stress, minor trauma, infections, or medical procedures, but often occur without any obvious cause [PMID:30138948].
Common locations for swelling include the skin (affecting hands, feet, face, genitals), the gastrointestinal tract (leading to severe abdominal pain, nausea, vomiting, and diarrhoea), and the upper airways (throat or larynx). Airway swelling is the most dangerous symptom, as it can block breathing and become life-threatening. Other symptoms can include prodromal signs like fatigue, tingling sensations, or a non-itchy rash before an attack begins.
Video: Genetics 101
Affected organs
HAE primarily affects tissues with loose connective tissue, leading to swelling. This includes the skin, particularly of the limbs, face, and genitals. Swelling in these areas is often disfiguring and can cause discomfort or limit movement.
Critically, the gastrointestinal tract is frequently affected, leading to severe abdominal pain, cramps, nausea, vomiting, and diarrhoea. These symptoms can sometimes be mistaken for other abdominal emergencies. Swelling of the upper airways, specifically the larynx (voice box), is also a significant concern, as it can lead to airway obstruction and is a medical emergency requiring prompt treatment.
Risks & severity
The severity of HAE can range from mild, infrequent swelling episodes to severe, frequent attacks that significantly impact quality of life. The greatest risk associated with HAE is laryngeal oedema (swelling of the voice box), which can lead to suffocation if not treated promptly [PMID:33671216]. The lifetime risk of at least one laryngeal oedema attack is substantial for individuals with HAE.
Abdominal attacks can be extremely painful and debilitating, often leading to hospitalisation. The onset of symptoms typically occurs in childhood or adolescence, though diagnosis can sometimes be delayed for many years. Untreated HAE can lead to chronic pain, anxiety, and a reduced quality of life due to the unpredictability and severity of the attacks.
Genetic causes
Hereditary angioedema is most commonly caused by pathogenic variants in the SERPING1 gene. This gene provides instructions for making a protein called C1-esterase inhibitor (C1-INH). C1-INH plays a crucial role in regulating several biological pathways, including the complement system, the coagulation system, and the contact system.
When a pathogenic variant in SERPING1 reduces the amount or function of C1-INH, these systems can become overactive. This overactivity leads to an uncontrolled release of bradykinin, a substance that causes blood vessels to leak fluid into surrounding tissues, resulting in the characteristic swelling episodes of HAE [PMID:30138948]. Most individuals with HAE type I have reduced levels of C1-INH, while those with HAE type II have normal levels but the C1-INH protein does not function correctly.
- SERPING1 serpin family G member 1
Inheritance pattern
Hereditary angioedema is inherited in an autosomal dominant pattern. This means that only one copy of the altered SERPING1 gene in each cell is sufficient to cause the condition. An affected individual has a 50% chance of passing the altered gene to each of their children, regardless of the child's sex.
In some cases, HAE can occur without a family history; this is known as a 'de novo' variant, where the genetic change happens for the first time in an individual. However, once a de novo variant occurs, the individual can then pass it on to their children in an autosomal dominant manner.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of HAE is typically suspected based on recurrent swelling episodes without urticaria (hives) and a family history. Confirmation involves specific blood tests to measure levels and function of C1-esterase inhibitor (C1-INH) [PMID:30138948]. Reduced C1-INH protein levels or reduced C1-INH function, along with low C4 complement levels, are characteristic findings.
Genetic testing for pathogenic variants in the SERPING1 gene can confirm the diagnosis, especially in cases where C1-INH levels are normal but suspicion remains high, or to identify the specific variant within families. In the UK, genetic testing for HAE falls under the NHS Genomic Medicine Service and is accessible via relevant R-codes following referral from a specialist, typically a clinical immunologist or a clinical geneticist. Genetic counsellors can provide support and information during the diagnostic process.
Management & lifestyle
Management of HAE focuses on preventing swelling attacks and treating acute episodes. Treatment plans are individualised and often involve a combination of approaches. Acute attacks, particularly laryngeal swelling, require urgent medical attention and specific medications designed to stop the swelling. These may include C1-INH concentrate or bradykinin receptor antagonists.
Long-term management strategies, known as prophylaxis, aim to reduce the frequency and severity of attacks. This can involve regular administration of C1-INH or other medications. Individuals with HAE are typically managed by specialists in immunology or allergy within the NHS. Genetic counselling is also an important part of care, providing information about inheritance, testing for family members, and reproductive options.
UK care pathway
In the UK, individuals suspected of having hereditary angioedema are typically referred to a specialist, such as a clinical immunologist or allergist, often through their GP. If HAE is suspected, the NHS Genomic Medicine Service provides access to diagnostic genetic testing for SERPING1 (under specific R-codes) following a specialist referral. A clinical genetics service can offer further support, including genetic counselling, to discuss the implications of a diagnosis for the individual and their wider family.
Frequently asked questions
Is hereditary angioedema an allergy?
No, hereditary angioedema is not an allergy. While it causes swelling, similar to some allergic reactions, HAE is a genetic condition caused by a problem with a specific protein, C1-esterase inhibitor. It does not involve the immune response typical of allergies and does not respond to antihistamines or adrenaline.
Are there different types of hereditary angioedema?
Yes, there are typically two main types of HAE due to SERPING1 variants: Type I, where there is a reduced amount of the C1-esterase inhibitor protein, and Type II, where the protein is present in normal amounts but does not function correctly. Both types lead to similar symptoms of swelling.
Can HAE be cured?
Currently, there is no cure for hereditary angioedema. However, there are effective treatments available to manage symptoms, prevent attacks, and stop acute swelling episodes once they begin. Ongoing research continues to explore new therapeutic options.
What should I do if I have a swelling attack?
If you experience a swelling attack, especially if it affects your throat or makes it difficult to breathe, you should seek immediate medical attention. Individuals with HAE usually have an emergency action plan and specific medications for acute attacks, and it is important to follow this plan as advised by your doctor.
Can family members be tested for hereditary angioedema?
Yes, once a diagnosis of HAE is confirmed in a family, genetic testing can be offered to at-risk relatives to determine if they have inherited the altered SERPING1 gene. This is often part of a genetic counselling process and can help identify affected individuals before symptoms become severe.
References
- Zafra H. Hereditary Angioedema: A Review. WMJ : official publication of the State Medical Society of Wisconsin. 2022. PMID: 35442579
- Busse PJ, Christiansen SC. Hereditary Angioedema. The New England journal of medicine. 2020. PMID: 32187470
- Betschel SD, Banerji A, Busse PJ. Hereditary Angioedema: A Review of the Current and Evolving Treatment Landscape. The journal of allergy and clinical immunology. In practice. 2023. PMID: 37116793
- Wilkerson RG, Moellman JJ. Hereditary Angioedema. Immunology and allergy clinics of North America. 2023. PMID: 37394258
- Wilkerson RG, Moellman JJ. Hereditary Angioedema. Emergency medicine clinics of North America. 2022. PMID: 34782094
- Gailani D. Hereditary angioedema and thrombosis. Blood. 2023. PMID: 37166925
- Bellanti JA, Settipane RA. Hereditary angioedema again revisited. Allergy and asthma proceedings. 2021. PMID: 33685554
- Bellanti JA, Settipane RA. Hereditary angioedema revisited. Allergy and asthma proceedings. 2018. PMID: 30153885