Hereditary Angioedema

Hereditary angioedema (HAE) is a rare genetic condition that causes sudden, severe swelling in different parts of the body. Though unpredictable and potentially life-threatening, advances in treatment now offer hope for people living with this challenging disorder.

What is Hereditary Angioedema?
Types of Hereditary Angioedema
Symptoms and Attacks
Causes and Genetics
How Common is HAE?
Diagnosis
Attack Triggers
Treatment Options
Living with HAE
Outlook

What is Hereditary Angioedema?

Hereditary angioedema (HAE) is a rare genetic condition that causes repeated episodes of severe swelling in different parts of the body. The swelling can affect the face, hands, feet, arms, legs, genitals, stomach, and throat^[1]. Unlike swelling caused by allergies, HAE does not cause itchy hives^[1].

The name tells us about the condition: “Angio-” refers to blood vessels, and “-edema” is the medical term for swelling due to fluid buildup within body tissues^[1]. This swelling occurs because fluid leaks out of tiny blood vessels in the body. The fluid builds up in nearby tissues, which can prevent blood or lymph from moving along as it should^[1].

HAE is congenital, which means a person is born with it^[1]. The condition is also called hereditary because it typically passes from parents to children through genes. However, in some cases, the genetic change happens spontaneously for unknown reasons, and as many as 25% of HAE cases result from a spontaneous mutation at conception^[4].

C1-Inhibitor Deficiency, C1-INH Deficiency

Types of Hereditary Angioedema

Healthcare providers divide HAE into different types based on levels and function of a protein called C1-Inhibitor (C1-INH)^[1]:

Type I HAE: This is the most common type, responsible for about 85% of all HAE cases. People with Type I HAE don’t make enough C1-INH protein. Without enough of this protein, inflammation and swelling can occur. Providers also call this type C1-INH deficiency^[1].
Type II HAE: This is the next most common type. The body can make enough C1-INH, but the protein doesn’t work properly^[1].
HAE with normal C1-INH: This type is the least common. People with this type have normal levels of C1-INH, and the protein functions normally. However, other genetic factors cause swelling to happen^[1]. Researchers have discovered that genetic defects in other genes, including Factor XII, Angiopoietin-1, Plasminogen, Kininogen-1, Myoferlin, and Heparan Sulfate-Glucosamine 3-Sulfotransferase 6, can cause HAE symptoms^[4].

All types of HAE behave similarly, causing episodes of swelling, even though the underlying protein problems differ^[3].

Symptoms and Attacks

The main symptom of HAE is swelling, which can happen in various parts of the body^[1]. These episodes are called HAE attacks. Symptoms vary from person to person and may include^[1]:

Visible swelling in the hands, feet, eyelids, lips, genitals, and buttocks
Swelling in the stomach and intestines, which can cause severe abdominal pain, nausea, vomiting, and diarrhea
Swelling in the mouth, throat, and airways, which can cause difficulty swallowing, tongue swelling, gasping sounds when breathing, hoarseness, and voice changes

Swelling in the throat is the most dangerous symptom of HAE. It can restrict breathing and become life-threatening. If you or someone with HAE struggles to breathe or swallow, call emergency services (911 in the U.S.) immediately^[1].

About one-third of people with HAE develop a flat, non-itchy rash called erythema marginatum during an attack^[2]. Some people notice warning signs before swelling begins, such as extreme fatigue, muscle aches, tingling, headache, mood changes, or belly pain^[6].

Symptoms of HAE typically begin in childhood and worsen during puberty^[2]. Symptoms can appear as early as age 2, and about half of all children with the most common types of HAE show symptoms by age 10^[1]. On average, untreated individuals have swelling episodes every 1 to 2 weeks, and most episodes last for about 3 to 4 days^[2]. The frequency and duration of attacks vary greatly among people with HAE, even among people in the same family^[2].

Causes and Genetics

HAE is caused by genetic changes (mutations) that affect proteins important for controlling inflammation and swelling in the body^[2].

In Types I and II HAE, mutations in the SERPING1 gene cause problems with the C1-INH protein. This protein normally blocks the activity of certain proteins that promote inflammation. More than 150 different mutations have been identified in patients with HAE^[3].

When the body doesn’t have enough normal C1-INH protein, it ends up with excessive amounts of a protein fragment called bradykinin. Bradykinin promotes inflammation by increasing the amount of fluid that leaks through the walls of blood vessels into body tissues. This fluid accumulation in body tissues causes the episodes of swelling seen in people with HAE^[2].

In HAE with normal C1-INH, mutations in other genes (such as the F12 gene) cause cells to produce proteins that are easier to activate than normal. This leads to greater-than-normal amounts of bradykinin being released, which causes swelling^[2].

HAE is inherited in an autosomal dominant pattern, which means one copy of an altered gene in each cell is sufficient to cause the disorder^[2]. If one parent has HAE, each child has a 50% chance of inheriting the condition^[4].

How Common is HAE?

HAE is rare. Types I and II HAE together affect about 1 in every 50,000 people worldwide^[1]^[2]. This means about 6,000 people in the United States have one of these types of HAE^[1]. Researchers don’t know exactly how many people have HAE with normal C1-INH, but they know it’s very rare^[1].

HAE affects men and women equally^[14]. Because HAE is so rare, it can take as long as a decade to obtain an accurate diagnosis after symptoms are first experienced^[4].

Diagnosis

Accurately diagnosing HAE can be difficult because the disease is rare and physicians often first rule out more common conditions with similar symptoms^[5]. Many healthcare providers have never encountered someone with the condition^[17].

In addition to a physical examination and medical history, HAE is diagnosed by measuring the level and function of C1-INH in the blood^[5]. Blood tests may include^[7]:

C1 inhibitor function
C1 inhibitor level
Complement component 4 (which may only be abnormal during an episode)

If you’ve had symptoms of HAE, your doctor may ask about your symptoms, where you’ve had swelling, how often swelling occurs, whether you’ve had any swelling in your face, neck, tongue or throat, any stomach problems or stomach surgery, and whether anyone in your family has a problem with swelling^[6].

Attack Triggers

HAE attacks can be unpredictable, and many occur without a known trigger^[2]. However, certain factors may trigger attacks by stimulating the body’s inflammatory response and increasing bradykinin production^[18]. Common triggers include^[4]^[6]:

Physical trauma or minor injury
Surgery or dental procedures
Stress or anxiety
Illnesses such as colds and flu
Certain medications, including some used for high blood pressure (such as ACE inhibitors)
Physical activities such as typing, hammering, or pushing a lawn mower
Hormonal changes in women, including menstrual periods, pregnancy, and the use of birth control or hormone replacement therapy containing estrogen

Although it’s not possible to avoid all triggers, keeping a journal of HAE attacks can help identify potential triggers and allow for lifestyle adjustments to avoid foods or activities that provoke attacks^[20].

Treatment Options

While there is no cure for HAE, various treatments can help manage the condition^[14]. Treatment strategies fall into two main categories: medications to prevent attacks and medications to treat acute attacks when they occur^[1].

Standard treatments used for allergic reactions—including antihistamines, corticosteroids, and epinephrine—do not work well for HAE^[7]. HAE requires specific medications designed for this condition.

Medications to Prevent HAE Attacks

Several medications are approved for preventing HAE attacks^[9]:

C1 Esterase Inhibitor concentrates: These medications replace the deficient protein. Examples include Cinryze (given intravenously) and Haegarda (given by injection under the skin). These can be self-administered by patients after proper training^[9].
Plasma kallikrein inhibitors: Lanadelumab (Takhzyro) is given by injection under the skin and works by blocking bradykinin generation. Donidalorsen (Dawnzera) reduces plasma kallikrein production^[9].
Oral medications: Berotralstat (Orladeyo) is taken by mouth once daily for patients 12 years and older^[8].

Medications to Treat Acute Attacks

Several medications are available to treat HAE attacks when they occur^[9]:

C1 Esterase Inhibitor (Berinert): Given intravenously to treat acute attacks in adults and children. Can be self-administered^[9].
Bradykinin B2 receptor antagonist: Icatibant (Firazyr) is delivered by injection under the skin for adults 18 years and older. It can be self-administered^[9].
Plasma kallikrein inhibitor: Ecallantide (Kalbitor) is delivered by injection under the skin for patients 12 years and older. Must be administered by a healthcare professional^[9].
Oral on-demand treatment: Sebetralstat (Ekterly) is the first oral medication approved for treating acute attacks in patients 12 years and older^[9].

With nine products currently approved by the FDA for preventing and treating HAE attacks, people with HAE and their physicians have options for developing a treatment plan tailored to meet each person’s unique needs^[9]. It is important to treat HAE attacks early for optimal response. The average time to noticeable improvement is often around 1 hour across these agents^[13].

Short-Term Prevention

Before surgeries and dental work, which can trigger HAE episodes, a doctor may prescribe a short-acting preventive treatment to reduce the likelihood of attacks^[20].

Living with HAE

Living with HAE can be challenging. People with the condition may face several difficulties^[15]:

Getting an accurate diagnosis
Having a rare illness that few people have heard of
Feeling isolated, lonely, or depressed
Finding a doctor who understands and treats HAE
Experiencing unpredictable, debilitating attacks
Participating in everyday activities

HAE can impact many aspects of daily life. In a 2017 survey of 445 patients, 34% reported that their physical health or emotional problems interfered with their ability to participate in social activities at least some of the time^[16]. Patients reported that HAE-related symptoms affected their work productivity and their ability to perform non-work-related activities^[16].

A higher frequency of attacks is associated with lower energy levels and greater difficulty performing basic daily activities. In studies, many patients reported that symptoms prevented them from applying to certain types of jobs, and nearly 80% reported missing work during severe attacks^[16].

Managing Stress

Because stress can trigger HAE attacks, managing stress is essential to reducing flare-ups and protecting well-being. Up to 21% of HAE attacks are triggered by emotional stress^[21]. Lifestyle adjustments that can help include^[20]:

Prioritizing sleep and self-care
Managing stress through relaxation techniques
Taking care to avoid exercise that is too strenuous and taking ample breaks during exercise
Keeping a journal to identify potential triggers
Adjusting the diet to avoid foods that trigger attacks

Pregnancy and Family Planning

Pregnant women with HAE don’t have a higher risk of infertility or miscarriage, and research shows that most women with HAE can have normal deliveries^[15]. However, the impact of HAE on pregnancy varies. Fluctuations in hormones associated with puberty, menstrual periods, contraceptive use, and menopause can impact the severity of HAE attacks^[15].

Because HAE is a genetic disorder, if you have HAE, your child has a 50% chance of inheriting the disease^[15]. If you’re pregnant and have HAE, you’ll need to discuss treatment options with your doctor. Certain medicines, such as anabolic steroids, aren’t safe for expecting mothers to take, but newer FDA-approved therapies may be an option^[15].

Support and Resources

Support groups and patient organizations can provide valuable resources and connections with others living with HAE. Organizations like the US Hereditary Angioedema Association offer educational materials, peer support, physician referrals, and guidance on access and reimbursement for HAE medicines^[17].

Outlook

HAE is a lifelong condition, but great strides have been made within the last decade to help manage it^[5]. Research continues to provide new treatments for people of all ages with HAE^[1].

With proper treatment and management, many people with HAE can lead full, active lives. The best approach to managing the disease is to be aware of early warning signs and triggers that can provoke an attack. Working with your healthcare team to develop a personalized management plan can empower you to live well with HAE^[5].

HAE can be life-threatening, and despite new treatments, airway swelling can still lead to death^[7]. This is why it’s critical to have an emergency action plan and to seek immediate medical attention if breathing difficulties occur.