What Is Hereditary Angioedema?

Hereditary angioedema (HAE) is a rare inherited genetic disorder that results in unexpected recurrent swellings under the skin, the lining of the gut, the lungs, and even other parts of the body.¹ HAE doesn’t involve a certain ethnic group, and it affects about 1 in 50,000 of the population. It is important to diagnose HAE early and treat it, if possible, as it could be a life-threatening emergency, particularly if there is any swelling in the throat, which can cut off the airways.¹

Understanding angioedema

HAE is characterised by asymmetric swelling of the face, lips, tongue, larynx, extremities and genitalia.^2-5 There are several chronic types of angiooedema - hereditary angiooedema, acquired angiooedema, medication-associated angiooedema, and idiopathic angiooedema.² 

Classification and pathophysiology

HAE is an autosomal dominant disorder linked to certain types of genetic mutations in factor XII, angiopoietin-1 and plasminogen gene, which causes C1 esterase inhibitor deficiency (C1-INH). As a result, these genetic mutations affect ‘Bradykinin”, a protein  that works as a strong vasodilator (blood vessels to elastically increase in diameter, increasing blood flow). Thus, when bradykinin is activated, it causes swelling under the skin and several parts of the body due to the increase in blood flow, which in individuals without HAE would be otherwise regulated.⁹

The classification of HAE depends on the presence of the particular molecule (C1 esterase inhibitor), which blocks bradykinin overproduction, thus not allowing swelling in individuals normally. HAE is classified based on the levels and normal functioning of this molecule.¹ 

Acquired Angioedema, unlike HAE, is a non-inherited disorder that is not linked to genetic mutations. Acquired angioedema is due to either consumption of the same molecule that blocks the overproduction of bradykinin (type 1) or its inactivation (type 2). Type 2 is an autoimmune disease in which the body destroys its production of C1 esterase inhibitors, which are normally produced in the body, by developing self-antibodies.⁶

Types of hereditary angioedema

Type 1 is a quantitative deficiency due to decreased amounts of C1-INH protein that causes lower than-normal levels. ¹

Type 2 is due to the reduced function of the C1-INH protein, which is caused by a structural defect in the way it is produced.¹

Type 3 is extremely rare; it is an oestrogen-dependent form due to a mutation in the coagulation factor XII gene, which occurs mainly in people assigned female at birth (PAFAB).¹

Clinical presentation

Symptoms

• Asymmetric swelling of the face, including lips and tongue, followed by swelling in other parts of the body, such as the larynx, extremities, and genitalia
• Swelling of the larynx can cause constrictions of the airways, leading to difficulty in breathing
• Swelling of the gastrointestinal tract can lead to severe abdominal pain, nausea, vomiting, and diarrhoea¹

Triggers of HAE attacks

• Stress
• Trauma
• Medical/surgical procedures, including dental surgery
• Hormonal changes: pregnancy, hormonal replacement therapy, menstruation, menopause, breastfeeding, contraceptive medication
• Infections: viral infections, flu, and colds
• Certain medications: ibuprofen and ACE inhibitors to maintain high blood pressure by increasing the severity and frequency of HAE attacks
• Repetitive actions: long periods of writing, typing, and hammering¹

Diagnosis of HAE

The following table illustrates the differential diagnosis of angiooedema:³

Legend for the table: ACEi = angiotensin-converting enzyme inhibitor (medication); ACEi-AAE = acquired angioedema associated with ACEis; ARB = angiotensin II receptor blocker (medication); FXII-HAE = hereditary angioedema with factor XII mutation; GI = gastrointestinal; NSAID = nonsteroidal anti-inflammatory drug(medication group).

Diagnosis of HAE with normal C1-INH (HAE FXII and HAE-Unknown)

Diagnosed based on a  history of recurrent angiooedema with the absence of urticaria or use of a medication known to cause angioedema. Lab tests commonly identify normal C4, C1-INH, and normal C1-INH functions.  

One of the following criteria should be present to firmly diagnose hereditary angioedema with normal C1-INH:¹

• Positive family history of angioedema and evidence of lack of chronic high-dose  antihistamines being able to act on the swelling  
• Proven factor XII mutation through investigation that links to the disease

History taking for suspected hereditary angioedema:

Diagnosis involves medical professionals commonly asking for oral history to check for recurrent angioedema episodes without urticaria and to determine any family history of the same.  History also involves asking for any recurrent abdominal pain without a certain/clear cause.  Lastly, the history of any family member diagnosed as having HAE.⁷

Laboratory tests

Blood tests to measure C4 levels, C1-INH levels, and C1-INH function.  Following this, results may be commonly interpreted as follows.³

If the C4 level is low, the C1-INH level is low, C1-INH function is low/normal.  This indicates type 1 HAE.

If the C4 level is low, the C1-INH level is normal, C1-INH function is low.  This indicates type 2 HAE.

Family history may not be present in up to 20% of HAE patients. Abdominal pain is the only clinical presentation of HAE, excluding other causes.  Family members should be screened even if they are asymptomatic.^7,9

While all three levels are measured following blood, the laboratory testing method of each might be different. For example, C4 and C1-INH levels are commonly measured through nephelometry. At the same time, C1-INH function is tested using enzyme-linked immunosorbent assay (ELISA).¹ 

For further details about these tests, we recommend asking your GP or your treating clinician since they may be able to guide you more specifically.

Genetic testing

Genetic technologies were implemented as an essential diagnostic tool for identifying additional genetic mutations not previously documented in non-C1-INH-HAE type; some examples would be next-generation sequencing (NGS), genome-wide sequencing and whole exome sequencing (WES).⁷

Moreover, NGS technology will allow us to study the whole gene SERPING1 with normal C1-INH to analyse its full length and identify more forms of HAE.^7,9

Management and treatment

Management involves either prophylaxis for future attacks to prevent any upcoming life-threatening attacks or treatment of acute attacks.¹ The aim is to reduce mortality and morbidity as much as possible.¹ 

Acute attack management:

It is classified into 3 types of medication used for treatment- plasma kallikrein inhibitor, selective bradykinin B2 receptor antagonist, and C1-INH protein replacement.

• Plasma kallikrein inhibitor: Ecallantide (Kalbitor) is administered by  injection under your skin
• Selective bradykinin B2 receptor antagonist: Icatibant (Firazyr) is also administered by  injection under your skin
• C1-INH protein replacement:  C1-INH concentrate recombinant (Ruconest) is administered by intravenous infusion¹

Prophylaxis

It is classified into three types of medication and their actions used for treatment -increased synthesis of C1-INH, C1-INH protein replacement, and plasma kallikrein inhibitor.

• Orally administered medication (Danazol) is used to increase the natural synthesis of C1-INH.¹
• A direct protein replacement, as C1-INH concentrate, plasma-derived (Cinryze) is administered by intravenous infusion.
• Plasma Kallikrein inhibitor, as Lanadelumab (Takhzyro) is administered by injection under the skin.

Avoiding triggers

The following measures can be taken to reduce and manage angioedema attacks:^3,9

• Manage stress by exercising regularly, following a healthy diet, keeping positive relationships, and spending time outdoors 
• Maintain short-term prophylactic treatment
• Get essential vaccinations such as flu vaccination
• Avoid any triggers to reduce the frequency of angioedema attacks

Research and future direction

The future research aims to study a wide variety of treatment options and is aimed at increasing the usage of genetic technologies such as next-generation sequencing (NGS) to find oral therapeutic agents as an alternative to intravenous administration of drugs, targeting specific proteins and enzymes linked to HAE disorder. Some of the targets for these medicines could be factor XII, which is not yet possible to target with current therapies. Gene therapy could also be a helpful alternative to enzyme inhibitors, which might cure the disorder rather than reducing angioedema attacks.¹

Summary and Conclusion

Primary care providers must be adept at distinguishing hereditary angioedema (HAE) from other types, particularly allergic angioedema, to prevent life-threatening outcomes and ensure appropriate therapeutic plans, thereby averting recurrent acute angioedema attacks. 

HAE-C1-INH type 1 results from a quantitative deficiency of C1-INH protein, while HAE-C1-INH type 2 is attributed to reduced C1-INH protein function. Normal C1-INH (HAE-nl-C1-INH) type is associated with genes coding for factor XII, plasminogen, and others, prompting ongoing research to identify additional relevant mutations. 

Management focuses on prophylactic treatment to prevent future attacks, involving lifestyle modifications, regular exercise, a healthy diet, stress management, and vaccination. Acute attacks are treated with plasma kallikrein inhibitors, bradykinin B2 receptor antagonists, and C1-INH protein replacement. 

Genetic testing, particularly next-generation sequencing, is emerging as a crucial tool for analyzing targeted therapeutic strategies and diagnosing HAE by studying the full length of relevant disorder genes, potentially leading to alternative treatments beyond parenteral injections.